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  • 1.
    Agullo, Luis
    et al.
    Univ Vic Cent Univ Catalonia UVIC UCC, Dept Syst Biol, U Sci Tech, Sagrada Familia 7, Vic 08500, Spain..
    Buch, Ignasi
    Hosp Del Mar Med Res Inst IMIM, Computat Biophys Lab, Barcelona 08003, Spain..
    Gutierrez-de-Teran, Hugo
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Garcia-Dorado, David
    Vall DHebron Res Inst VHIR, Cardiocirculatory Pathol Grp, Barcelona 08035, Spain..
    Villa-Freixa, Jordi
    Univ Vic Cent Univ Catalonia UVIC UCC, Dept Syst Biol, U Sci Tech, Sagrada Familia 7, Vic 08500, Spain..
    Computational exploration of the binding mode of heme-dependent stimulators into the active catalytic domain of soluble guanylate cyclase2016In: Proteins: Structure, Function, and Bioinformatics, ISSN 0887-3585, E-ISSN 1097-0134, Vol. 84, no 10, p. 1534-1548Article in journal (Refereed)
    Abstract [en]

    Soluble guanylate cyclase (sGC), the main target of nitric oxide (NO), has been proven to have a significant role in coronary artery disease, pulmonary hypertension, erectile dysfunction, and myocardial infarction. One of its agonists, BAY 41-2272 (Riociguat), has been recently approved for treatment of pulmonary arterial hypertension (PHA), while some others are in clinical phases of development. However, the location of the binding sites for the two known types of agonists, heme-dependent stimulators and heme-independent activators, is a matter of debate, particularly for the first group where both a location on the regulatory (H-NOX) and on the catalytic domain have been suggested by different authors. Here, we address its potential location on the catalytic domain, the unique well characterized at the structural level, by an in silico approach. Homology models of the catalytic domain of sGC in inactive or active conformations were constructed using the structure of previously described crystals of the catalytic domains of inactive sGCs (2WZ1, 3ET6) and of active adenylate cyclase (1CJU). Each model was submitted to six independent molecular dynamics simulations of about 1 s. Docking of YC-1, a classic heme-dependent stimulator, to all frames of representative trajectories of inactive and active conformations, followed by calculation of absolute binding free energies with the linear interaction energy (LIE) method, revealed a potential high-affinity binding site on the active structure. The site, located between the pseudo-symmetric and the catalytic site just over the loop (2)-(3), does not overlap with the forskolin binding site on adenylate cyclases.

  • 2.
    Aken, Bronwen L.
    et al.
    European Bioinformat Inst Wellcome Genome Campus, European Mol Biol Lab, Cambridge CB10 1SD, England.;Wellcome Trust Sanger Inst Wellcome Genome Campus, Cambridge CB10 1SA, England..
    Ayling, Sarah
    Wellcome Trust Sanger Inst Wellcome Genome Campus, Cambridge CB10 1SA, England.;Genome Anal Ctr, Norwich Res Pk, Norwich NR4 7UH, Norfolk, England..
    Barrell, Daniel
    European Bioinformat Inst Wellcome Genome Campus, European Mol Biol Lab, Cambridge CB10 1SD, England.;Wellcome Trust Sanger Inst Wellcome Genome Campus, Cambridge CB10 1SA, England.;Eagle Genom Ltd, Babraham Res Campus, Cambridge CB22 3AT, England..
    Clarke, Laura
    Wellcome Trust Sanger Inst Wellcome Genome Campus, Cambridge CB10 1SA, England.;European Bioinformat Inst, European Mol Biol Lab, Wellcome Genome Campus, Cambridge CB10 1SD, England..
    Curwen, Valery
    Wellcome Trust Sanger Inst Wellcome Genome Campus, Cambridge CB10 1SA, England..
    Fairley, Susan
    Wellcome Trust Sanger Inst Wellcome Genome Campus, Cambridge CB10 1SA, England.;European Bioinformat Inst, European Mol Biol Lab, Wellcome Genome Campus, Cambridge CB10 1SD, England..
    Banet, Julio Fernandez
    Wellcome Trust Sanger Inst Wellcome Genome Campus, Cambridge CB10 1SA, England.;Pfizer Inc, 10646 Sci Ctr Dr, San Diego, CA 92121 USA..
    Billis, Konstantinos
    European Bioinformat Inst Wellcome Genome Campus, European Mol Biol Lab, Cambridge CB10 1SD, England.;Wellcome Trust Sanger Inst Wellcome Genome Campus, Cambridge CB10 1SA, England..
    Giron, Carlos Garcia
    European Bioinformat Inst Wellcome Genome Campus, European Mol Biol Lab, Cambridge CB10 1SD, England.;Wellcome Trust Sanger Inst Wellcome Genome Campus, Cambridge CB10 1SA, England..
    Hourlier, Thibaut
    European Bioinformat Inst Wellcome Genome Campus, European Mol Biol Lab, Cambridge CB10 1SD, England.;Wellcome Trust Sanger Inst Wellcome Genome Campus, Cambridge CB10 1SA, England..
    Howe, Kevin
    Wellcome Trust Sanger Inst Wellcome Genome Campus, Cambridge CB10 1SA, England.;European Bioinformat Inst, European Mol Biol Lab, Wellcome Genome Campus, Cambridge CB10 1SD, England..
    Kähäri, Andreas
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Wellcome Trust Sanger Inst Wellcome Genome Campus, Cambridge CB10 1SA, England.
    Kokocinski, Felix
    Wellcome Trust Sanger Inst Wellcome Genome Campus, Cambridge CB10 1SA, England..
    Martin, Fergal J.
    European Bioinformat Inst Wellcome Genome Campus, European Mol Biol Lab, Cambridge CB10 1SD, England.;Wellcome Trust Sanger Inst Wellcome Genome Campus, Cambridge CB10 1SA, England..
    Murphy, Daniel N.
    European Bioinformat Inst Wellcome Genome Campus, European Mol Biol Lab, Cambridge CB10 1SD, England.;Wellcome Trust Sanger Inst Wellcome Genome Campus, Cambridge CB10 1SA, England..
    Nag, Rishi
    European Bioinformat Inst Wellcome Genome Campus, European Mol Biol Lab, Cambridge CB10 1SD, England.;Wellcome Trust Sanger Inst Wellcome Genome Campus, Cambridge CB10 1SA, England..
    Ruffier, Magali
    Wellcome Trust Sanger Inst Wellcome Genome Campus, Cambridge CB10 1SA, England.;European Bioinformat Inst, European Mol Biol Lab, Wellcome Genome Campus, Cambridge CB10 1SD, England..
    Schuster, Michael
    European Bioinformat Inst Wellcome Genome Campus, European Mol Biol Lab, Cambridge CB10 1SD, England.;Austrian Acad Sci, CeMM Res Ctr Mol Med, A-1090 Vienna, Austria..
    Tang, Y. Amy
    Wellcome Trust Sanger Inst Wellcome Genome Campus, Cambridge CB10 1SA, England.;European Bioinformat Inst, European Mol Biol Lab, Wellcome Genome Campus, Cambridge CB10 1SD, England..
    Vogel, Jan-Hinnerk
    Wellcome Trust Sanger Inst Wellcome Genome Campus, Cambridge CB10 1SA, England.;Genentech Inc, 1 DNAWay, San Francisco, CA 94080 USA..
    White, Simon
    Wellcome Trust Sanger Inst Wellcome Genome Campus, Cambridge CB10 1SA, England.;Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA..
    Zadissa, Amonida
    Wellcome Trust Sanger Inst Wellcome Genome Campus, Cambridge CB10 1SA, England.;European Bioinformat Inst, European Mol Biol Lab, Wellcome Genome Campus, Cambridge CB10 1SD, England..
    Flicek, Paul
    European Bioinformat Inst Wellcome Genome Campus, European Mol Biol Lab, Cambridge CB10 1SD, England.;Wellcome Trust Sanger Inst Wellcome Genome Campus, Cambridge CB10 1SA, England..
    Searle, Stephen M. J.
    Wellcome Trust Sanger Inst Wellcome Genome Campus, Cambridge CB10 1SA, England..
    The Ensembl gene annotation system2016In: Database: The Journal of Biological Databases and Curation, ISSN 1758-0463, E-ISSN 1758-0463, article id baw093Article in journal (Refereed)
    Abstract [en]

    The Ensembl gene annotation system has been used to annotate over 70 different vertebrate species across a wide range of genome projects. Furthermore, it generates the automatic alignment-based annotation for the human and mouse GENCODE gene sets. The system is based on the alignment of biological sequences, including cDNAs, proteins and RNA-seq reads, to the target genome in order to construct candidate transcript models. Careful assessment and filtering of these candidate transcripts ultimately leads to the final gene set, which is made available on the Ensembl website. Here, we describe the annotation process in detail.

  • 3.
    Ameur, Adam
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Natl Genom Infrastruct, Sci Life Lab, Stockholm, Sweden..
    Dahlberg, Johan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Natl Genom Infrastruct, Sci Life Lab, Stockholm, Sweden.
    Olason, Pall
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. Natl Bioinformat Infrastruct, Sci Life Lab, Stockholm, Sweden..
    Vezzi, Francesco
    Natl Genom Infrastruct, Sci Life Lab, Stockholm, Sweden.;Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Stockholm, Sweden..
    Karlsson, Robert
    Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Martin, Marcel
    Natl Bioinformat Infrastruct, Sci Life Lab, Stockholm, Sweden.;Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Stockholm, Sweden..
    Viklund, Johan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Natl Bioinformat Infrastruct, Sci Life Lab, Stockholm, Sweden..
    Kähäri, Andreas
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Natl Bioinformat Infrastruct, Sci Life Lab, Stockholm, Sweden..
    Lundin, Par
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Stockholm, Sweden..
    Che, Huiwen
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Thutkawkorapin, Jessada
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Eisfeldt, Jesper
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Lampa, Samuel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Natl Bioinformat Infrastruct, Sci Life Lab, Stockholm, Sweden.
    Dahlberg, Mats
    Natl Bioinformat Infrastruct, Sci Life Lab, Stockholm, Sweden.;Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Stockholm, Sweden..
    Hagberg, Jonas
    Natl Bioinformat Infrastruct, Sci Life Lab, Stockholm, Sweden.;Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Stockholm, Sweden..
    Jareborg, Niclas
    Natl Bioinformat Infrastruct, Sci Life Lab, Stockholm, Sweden.;Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Stockholm, Sweden..
    Liljedahl, Ulrika
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Natl Genom Infrastruct, Sci Life Lab, Stockholm, Sweden.
    Jonasson, Inger
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Natl Genom Infrastruct, Sci Life Lab, Stockholm, Sweden..
    Johansson, Åsa
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Feuk, Lars
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Lundeberg, Joakim
    Natl Genom Infrastruct, Sci Life Lab, Stockholm, Sweden.;Royal Inst Technol, Div Gene Technol, Sch Biotechnol, Sci Life Lab, Stockholm, Sweden..
    Syvänen, Ann-Christine
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Natl Genom Infrastruct, Sci Life Lab, Stockholm, Sweden.
    Lundin, Sverker
    Royal Inst Technol, Div Gene Technol, Sch Biotechnol, Sci Life Lab, Stockholm, Sweden..
    Nilsson, Daniel
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Nystedt, Björn
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Evolution. Natl Bioinformat Infrastruct, Sci Life Lab, Stockholm, Sweden..
    Magnusson, Patrik K. E.
    Natl Genom Infrastruct, Sci Life Lab, Stockholm, Sweden.;Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden..
    Gyllensten, Ulf B.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    SweGen: a whole-genome data resource of genetic variability in a cross-section of the Swedish population2017In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 25, no 11, p. 1253-1260Article in journal (Refereed)
    Abstract [en]

    Here we describe the SweGen data set, a comprehensive map of genetic variation in the Swedish population. These data represent a basic resource for clinical genetics laboratories as well as for sequencing-based association studies by providing information on genetic variant frequencies in a cohort that is well matched to national patient cohorts. To select samples for this study, we first examined the genetic structure of the Swedish population using high-density SNP-array data from a nation-wide cohort of over 10 000 Swedish-born individuals included in the Swedish Twin Registry. A total of 1000 individuals, reflecting a cross-section of the population and capturing the main genetic structure, were selected for whole-genome sequencing. Analysis pipelines were developed for automated alignment, variant calling and quality control of the sequencing data. This resulted in a genome-wide collection of aggregated variant frequencies in the Swedish population that we have made available to the scientific community through the website https://swefreq.nbis.se. A total of 29.2 million single-nucleotide variants and 3.8 million indels were detected in the 1000 samples, with 9.9 million of these variants not present in current databases. Each sample contributed with an average of 7199 individual-specific variants. In addition, an average of 8645 larger structural variants (SVs) were detected per individual, and we demonstrate that the population frequencies of these SVs can be used for efficient filtering analyses. Finally, our results show that the genetic diversity within Sweden is substantial compared with the diversity among continental European populations, underscoring the relevance of establishing a local reference data set.

  • 4.
    Asp, Michaela
    et al.
    KTH Royal Inst Technol, Div Gene Technol, Sci Life Lab, Stockholm, Sweden..
    Salmen, Fredrik
    KTH Royal Inst Technol, Div Gene Technol, Sci Life Lab, Stockholm, Sweden..
    Ståhl, Patrik L.
    Karolinska Inst, Dept Cell & Mol Biol, Stockholm, Sweden..
    Vickovic, Sanja
    KTH Royal Inst Technol, Div Gene Technol, Sci Life Lab, Stockholm, Sweden..
    Felldin, Ulrika
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Löfling, Marie
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Navarro, Jose Fernandez
    Karolinska Inst, Dept Cell & Mol Biol, Stockholm, Sweden..
    Maaskola, Jonas
    KTH Royal Inst Technol, Div Gene Technol, Sci Life Lab, Stockholm, Sweden..
    Eriksson, Maria J.
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Clin Physiol, Stockholm, Sweden..
    Persson, Bengt
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Karolinska Inst, Dept Med Biochem & Biophys, Sci Life Lab, Stockholm, Sweden..
    Corbascio, Matthias
    Karolinska Univ Hosp, Dept Cardiothorac Surg & Anesthesiol, Solna, Sweden..
    Persson, Hans
    Danderyd Hosp, Dept Cardiol, Stockholm, Sweden.;Karolinska Inst, Danderyd Hosp, Dept Clin Sci, Stockholm, Sweden..
    Linde, Cecilia
    Karolinska Inst, Dept Med, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Cardiol, Stockholm, Sweden..
    Lundeberg, Joakim
    KTH Royal Inst Technol, Div Gene Technol, Sci Life Lab, Stockholm, Sweden..
    Spatial detection of fetal marker genes expressed at low level in adult human heart tissue2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 12941Article in journal (Refereed)
    Abstract [en]

    Heart failure is a major health problem linked to poor quality of life and high mortality rates. Hence, novel biomarkers, such as fetal marker genes with low expression levels, could potentially differentiate disease states in order to improve therapy. In many studies on heart failure, cardiac biopsies have been analyzed as uniform pieces of tissue with bulk techniques, but this homogenization approach can mask medically relevant phenotypes occurring only in isolated parts of the tissue. This study examines such spatial variations within and between regions of cardiac biopsies. In contrast to standard RNA sequencing, this approach provides a spatially resolved transcriptome- and tissue-wide perspective of the adult human heart, and enables detection of fetal marker genes expressed by minor subpopulations of cells within the tissue. Analysis of patients with heart failure, with preserved ejection fraction, demonstrated spatially divergent expression of fetal genes in cardiac biopsies.

  • 5.
    Azuaje, Jhonny
    et al.
    Univ Santiago de Compostela, Ctr Singular Invest Quim Biol & Mat Mol CIQUS, Santiago De Compostela 15782, Spain.;Univ Santiago de Compostela, Fac Farm, Dept Quim Organ, Santiago De Compostela 15782, Spain..
    Jespers, Willem
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Yaziji, Vicente
    Univ Santiago de Compostela, Ctr Singular Invest Quim Biol & Mat Mol CIQUS, Santiago De Compostela 15782, Spain.;Univ Santiago de Compostela, Fac Farm, Dept Quim Organ, Santiago De Compostela 15782, Spain..
    Mallo, Ana
    Univ Santiago de Compostela, Ctr Singular Invest Quim Biol & Mat Mol CIQUS, Santiago De Compostela 15782, Spain.;Univ Santiago de Compostela, Fac Farm, Dept Quim Organ, Santiago De Compostela 15782, Spain..
    Majellaro, Maria
    Univ Santiago de Compostela, Ctr Singular Invest Quim Biol & Mat Mol CIQUS, Santiago De Compostela 15782, Spain.;Univ Santiago de Compostela, Fac Farm, Dept Quim Organ, Santiago De Compostela 15782, Spain..
    Caamano, Olga
    Univ Santiago de Compostela, Fac Farm, Dept Quim Organ, Santiago De Compostela 15782, Spain..
    Loza, Maria I.
    Univ Santiago de Compostela, Ctr Singular Invest Med Mol & Enfermedades Cronic, Santiago De Compostela 15782, Spain..
    Cadavid, Maria I.
    Univ Santiago de Compostela, Ctr Singular Invest Med Mol & Enfermedades Cronic, Santiago De Compostela 15782, Spain..
    Brea, Jose
    Univ Santiago de Compostela, Ctr Singular Invest Med Mol & Enfermedades Cronic, Santiago De Compostela 15782, Spain..
    Åqvist, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Sotelo, Eddy
    Univ Santiago de Compostela, Ctr Singular Invest Quim Biol & Mat Mol CIQUS, Santiago De Compostela 15782, Spain.;Univ Santiago de Compostela, Fac Farm, Dept Quim Organ, Santiago De Compostela 15782, Spain..
    Gutiérrez-de-Terán, Hugo
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Effect of Nitrogen Atom Substitution in A(3) Adenosine Receptor Binding: N-(4,6-Diarylpyridin-2-yl)acetamides as Potent and Selective Antagonists2017In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 60, no 17, p. 7502-7511Article in journal (Refereed)
    Abstract [en]

    We report the first family of 2-acetamidopyridines as potent and selective A, adenosine receptor (AR) antagonists. The computer -assisted design was focused on the bioisosteric replacement of the N1 atom by a CH group in a previous series of diarylpyrimidines. Some of the generated 2-acetamidopyridines elicit an antagonistic effect with excellent affinity (K-j < 10 nM) and outstanding selectivity profiles, providing an alternative and simpler chemical scaffold to the parent series of diarylpyrimidines. In addition, using molecular dynamics and free energy perturbation simulations, we elucidate the effect of the second nitrogen of the parent diarylpyrimidines, which is revealed as a stabilizer of a water network in the binding site. The discovery of 2,6-diaryl-2-acetamidopyridines represents a step forward in the search of chemically simple, potent, and selective antagonists for the hA(3)AR, and exemplifies the benefits of a joint theoretical- experimental approach to identify novel hA(3)AR antagonists through succinct and efficient synthetic methodologies.

  • 6.
    Baltzer, Nicholas
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Stockholm County, Sweden.
    Sundström, Karin
    Karolinska Inst, Dept Lab Med, Stockholm, Stockholm Count, Sweden..
    Nygård, Jan F.
    Canc Registry Norway, Dept Registry Informat, Oslo, Oslo County, Norway..
    Dillner, Joakim
    Karolinska Inst, Dept Lab Med, Stockholm, Stockholm Count, Sweden..
    Komorowski, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Polish Acad Sci, Inst Comp Sci, Warsaw, Warsaw County, Poland..
    Risk stratification in cervical cancer screening by complete screening history: Applying bioinformatics to a general screening population2017In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 141, no 1, p. 200-209Article in journal (Refereed)
    Abstract [en]

    Women screened for cervical cancer in Sweden are currently treated under a one-size-fits-all programme, which has been successful in reducing the incidence of cervical cancer but does not use all of the participants' available medical information. This study aimed to use women's complete cervical screening histories to identify diagnostic patterns that may indicate an increased risk of developing cervical cancer. A nationwide case-control study was performed where cervical cancer screening data from 125,476 women with a maximum follow-up of 10 years were evaluated for patterns of SNOMED diagnoses. The cancer development risk was estimated for a number of different screening history patterns and expressed as Odds Ratios (OR), with a history of 4 benign cervical tests as reference, using logistic regression. The overall performance of the model was moderate (64% accuracy, 71% area under curve) with 61-62% of the study population showing no specific patterns associated with risk. However, predictions for high-risk groups as defined by screening history patterns were highly discriminatory with ORs ranging from 8 to 36. The model for computing risk performed consistently across different screening history lengths, and several patterns predicted cancer outcomes. The results show the presence of risk-increasing and risk-decreasing factors in the screening history. Thus it is feasible to identify subgroups based on their complete screening histories. Several high-risk subgroups identified might benefit from an increased screening density. Some low-risk subgroups identified could likely have a moderately reduced screening density without additional risk.

  • 7.
    Barrozo, Alexandre
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Liao, Qinghua
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structural Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Esguerra, Mauricio
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Marloie, Gael
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Florian, Jan
    Loyola Univ Chicago, Dept Chem & Biochem, Chicago, IL 60660 USA..
    Williams, Nicholas H.
    Univ Sheffield, Dept Chem, Sheffield S3 7HF, S Yorkshire, England..
    Kamerlin, Shina C. Lynn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Computer simulations of the catalytic mechanism of wild-type and mutant beta-phosphoglucomutase2018In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 16, no 12, p. 2060-2073Article in journal (Refereed)
    Abstract [en]

    beta-Phosphoglucomutase (beta-PGM) has served as an important model system for understanding biological phosphoryl transfer. This enzyme catalyzes the isomerization of beta-glucose-1-phosphate to -glucose-6-phosphate in a two-step process proceeding via a bisphosphate intermediate. The conventionally accepted mechanism is that both steps are concerted processes involving acid-base catalysis from a nearby aspartate (D10) side chain. This argument is supported by the observation that mutation of D10 leaves the enzyme with no detectable activity. However, computational studies have suggested that a substrate-assisted mechanism is viable for many phosphotransferases. Therefore, we carried out empirical valence bond (EVB) simulations to address the plausibility of this mechanistic alternative, including its role in the abolished catalytic activity of the D10S, D10C and D10N point mutants of beta-PGM. In addition, we considered both of these mechanisms when performing EVB calculations of the catalysis of the wild type (WT), H20A, H20Q, T16P, K76A, D170A and E169A/D170A protein variants. Our calculated activation free energies confirm that D10 is likely to serve as the general base/acid for the reaction catalyzed by the WT enzyme and all its variants, in which D10 is not chemically altered. Our calculations also suggest that D10 plays a dual role in structural organization and maintaining electrostatic balance in the active site. The correct positioning of this residue in a catalytically competent conformation is provided by a functionally important conformational change in this enzyme and by the extensive network of H-bonding interactions that appear to be exquisitely preorganized for the transition state stabilization.

  • 8.
    Bashardanesh, Zahedeh
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Lötstedt, Per
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Division of Scientific Computing. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Numerical Analysis.
    Efficient Green's function reaction dynamics (GFRD) simulations for diffusion-limited, reversible reactions2018In: Journal of Computational Physics, ISSN 0021-9991, E-ISSN 1090-2716, Vol. 357, p. 78-99Article in journal (Refereed)
  • 9.
    Bashardanesh, Zahedeh
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    van der Spoel, David
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Impact of Dispersion Coefficient on Simulations of Proteins and Organic Liquids2018In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 122, no 33, p. 8018-8027Article in journal (Refereed)
    Abstract [en]

    In the context of studies of proteins under crowding conditions, it was found that there is a tendency of simulated proteins to coagulate in a seemingly unphysical manner. This points to an imbalance in the protein-protein or protein-water interactions. One way to resolve this is to strengthen the protein-water Lennard-Jones interactions. However, it has also been suggested that dispersion interactions may have been systematically overestimated in force fields due to parameterization with a short cutoff. Here, we test this proposition by performing simulations of liquids and of proteins in solution with systematically reduced C-6 (dispersion constant in a 12-6 Lennard-Jones potential) and evaluate the properties. We find that simulations of liquids with either a dispersion correction or explicit long-range Lennard-Jones interactions need little or no correction to the dispersion constant to reproduce the experimental density. For simulations of proteins, a significant reduction in the dispersion constant is needed to reduce the coagulation, however. Because the protein- and liquid force fields share atom types, at least to some extent, another solution for the coagulation problem may be needed, either through including explicit polarization or through strengthening protein-water interactions.

  • 10.
    Bauer, Paul
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Barrozo, Alexandre
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology.
    Amrein, Beat Anton
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology.
    Purg, Miha
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology.
    Esguerra, Mauricio
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Wilson, Philippe
    De Montfort University Leicester, School of Pharmacy .
    Åqvist, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Major, Dan Thomas
    Department of Chemistry, The Lise Meitner-Minerva Center of Computational Quantum Chemistry, Bar-Ilan University, Ramat-Gan 52900, Israel.
    Kamerlin, Shina Caroline Lynn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology.
    Q Version 6, a comprehensive toolkit for empirical valence bond and related free energy calculations.Manuscript (preprint) (Other academic)
  • 11.
    Bauer, Paul
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Barrozo, Alexandre
    Department of Chemistry, University of Southern California, SGM 418, 3620 McClintock Ave., Los Angeles, CA 90089-1062, United StatesDepartment of Chemistry, University of Southern California, SGM 418, 3620 McClintock Ave., Los Angeles, CA 90089-1062, United States.
    Purg, Miha
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Amrein, Beat Anton
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Esguerra, Mauricio
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Wilson, Philippe Barrie
    Leicester School of Pharmacy, De Montfort University, The Gateway, Leicester LE1 9BH, UK.
    Major, Dan Thomas
    Department of Chemistry, Bar-Ilan University, Ramat-Gan 52900, Israel.
    Aqvist, Johan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Kamerlin, Shina C. Lynn
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structural Biology.
    Q6: A comprehensive toolkit for empirical valence bond and related free energy calculations2018In: Software Quality Professional, ISSN 1522-0540, E-ISSN 2352-7110, SoftwareX, ISSN 2352-7110Article in journal (Refereed)
    Abstract [en]

    Atomistic simulations have become one of the main approaches to study the chemistry and dynamicsof biomolecular systems in solution. Chemical modelling is a powerful way to understand biochemistry,with a number of different programs available to perform specialized calculations. We present here Q6, anew version of the Q software package, which is a generalized package for empirical valence bond, linearinteraction energy, and other free energy calculations. In addition to general technical improvements, Q6extends the reach of the EVB implementation to fast approximations of quantum effects, extended solventdescriptions and quick estimation of the contributions of individual residues to changes in the activationfree energy of reactions.

  • 12.
    Behzadi, Hadi
    et al.
    Department of Physical Chemistry, Faculty of Chemistry, Kharazmi University, 15719-14911, Tehran, Iran.
    Manzetti, Sergio
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Fjordforsk AS, N-6894 Midtun, Vangsnes, Norway.
    Darghai, Mayram
    Department of Chemistry, Faculty of Science, Imam Khomeini International University, Qazvin, Iran.
    Roonasi, Payman
    Department of Physical Chemistry, Faculty of Chemistry, Kharazmi University, 15719-14911, Tehran, Iran.
    Khalilnia, Zahra
    Department of Physical Chemistry, Faculty of Chemistry, Kharazmi University, 15719-14911, Tehran, Iran.
    Application of calculated NMR parameters, aromaticity indices and wavefunction properties for evaluation of corrosion inhibition efficiency of pyrazine inhibitors2018In: Journal of Molecular Structure: THEOCHEM, ISSN 0166-1280, Vol. 1151, p. 34-40Article in journal (Refereed)
  • 13.
    Behzadi, Hadi
    et al.
    Kharazmi Univ, Fac Chem, Dept Phys Chem, Tehran, Iran.
    Roonasi, Payman
    Kharazmi Univ, Fac Chem, Dept Phys Chem, Tehran, Iran.
    Taghipour, Khatoon Assle
    Kharazmi Univ, Fac Chem, Dept Phys Chem, Tehran, Iran.
    van der Spoel, David
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Manzetti, Sergio
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Fjordforsk AS Inst Sci & Technol, N-6894 Midtun, Vangsnes, Norway.
    Relationship between electronic properties and drug activity of seven quinoxaline compounds: A DFT study2015In: Journal of Molecular Structure, ISSN 0022-2860, E-ISSN 1872-8014, Vol. 1091, p. 196-202Article in journal (Refereed)
    Abstract [en]

    The quantum chemical calculations at the DFT/B3LYP level of theory were carried out on seven quinoxaline compounds, which have been synthesized as anti-Mycobacterium tuberculosis agents. Three conformers were optimized for each compound and the lowest energy structure was found and used in further calculations. The electronic properties including E-HOMO, E-LUMO and related parameters as well as electron density around oxygen and nitrogen atoms were calculated for each compound. The relationship between the calculated electronic parameters and biological activity of the studied compounds were investigated. Six similar quinoxaline derivatives with possible more drug activity were suggested based on the calculated electronic descriptors. A mechanism was proposed and discussed based on the calculated electronic parameters and bond dissociation energies.

  • 14.
    Bellissent-Funel, Marie-Claire
    et al.
    CEA Saclay, CNRS, Lab Leon Brillouin, F-91191 Gif Sur Yvette, France..
    Hassanali, Ali
    Abdus Salaam Int Ctr Theoret Phys, Condensed Matter & Stat Phys, I-34151 Trieste, Italy..
    Havenith, Martina
    Ruhr Univ Bochum, Fac Chem & Biochem, Univ Str 150 Bldg NC 7-72, D-44780 Bochum, Germany..
    Henchman, Richard
    Univ Manchester, Manchester Inst Biotechnol, 131 Princess St, Manchester M1 7DN, Lancs, England..
    Pohl, Peter
    Johannes Kepler Univ Linz, Gruberstr 40, A-4020 Linz, Austria..
    Sterpone, Fabio
    Inst Biol Physicochim, Lab Biochim Theor, 13 Rue Pierre & Marie Curie, F-75005 Paris, France..
    van der Spoel, David
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Xu, Yao
    Ruhr Univ Bochum, Fac Chem & Biochem, Univ Str 150 Bldg NC 7-72, D-44780 Bochum, Germany..
    Garcia, Angel E.
    Los Alamos Natl Lab, Ctr Non Linear Studies, Los Alamos, NM 87545 USA..
    Water Determines the Structure and Dynamics of Proteins2016In: Chemical Reviews, ISSN 0009-2665, E-ISSN 1520-6890, Vol. 116, no 13, p. 7673-7697Article, review/survey (Refereed)
    Abstract [en]

    Water is an essential participant in the stability, structure, dynamics, and function of proteins and other biomolecules. Thermodynamically, changes in the aqueous environment affect the stability of biomolecules. Structurally, water participates chemically in the catalytic function of proteins and nucleic acids and physically in the collapse of the protein chain during folding through hydrophobic collapse and mediates binding through the hydrogen bond in complex formation. Water is a partner that slaves the dynamics of proteins, and water interaction with proteins affect their dynamics. Here we provide a review of the experimental and computational advances over the past decade in understanding the role of water in the dynamics, structure, and function of proteins. We focus on the combination of X-ray and neutron crystallography, NMR, terahertz spectroscopy, mass spectroscopy, thermodynamics, and computer simulations to reveal how water assist proteins in their function. The recent advances in computer simulations and the enhanced sensitivity of experimental tools promise major advances in the understanding of protein dynamics, and water surely will be a protagonist.

  • 15.
    Bharate, Sandip B.
    et al.
    CSIR Indian Inst Integrat Med, Div Med Chem, Canal Rd, Jammu 180001, Jammu & Kashmir, India.;CSIR Indian Inst Integrat Med, Acad Sci & Innovat Res AcSIR, Canal Rd, Jammu 180001, Jammu & Kashmir, India..
    Singh, Baljinder
    CSIR Indian Inst Integrat Med, Nat Prod Chem Div, Canal Rd, Jammu 180001, Jammu & Kashmir, India..
    Kachler, Sonja
    Univ Wurzburg, Inst Pharmakol & Toxikol, Versbacher Str 9, D-97078 Wurzburg, Germany..
    Oliveira, Ana
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Kumar, Vikas
    CSIR Indian Inst Integrat Med, Acad Sci & Innovat Res AcSIR, Canal Rd, Jammu 180001, Jammu & Kashmir, India.;CSIR Indian Inst Integrat Med, Preformulat Lab, Canal Rd, Jammu 180001, Jammu & Kashmir, India..
    Bharate, Sonali S.
    CSIR Indian Inst Integrat Med, Preformulat Lab, Canal Rd, Jammu 180001, Jammu & Kashmir, India..
    Vishwakarma, Ram A.
    CSIR Indian Inst Integrat Med, Div Med Chem, Canal Rd, Jammu 180001, Jammu & Kashmir, India.;CSIR Indian Inst Integrat Med, Acad Sci & Innovat Res AcSIR, Canal Rd, Jammu 180001, Jammu & Kashmir, India..
    Klotz, Karl-Norbert
    Univ Wurzburg, Inst Pharmakol & Toxikol, Versbacher Str 9, D-97078 Wurzburg, Germany..
    de Teran, Hugo Gutierrez
    Uppsala Univ, Dept Cell & Mol Biol, Box 596, SE-75124 Uppsala, Sweden..
    Discovery of 7-(Prolinol-N-yl)-2-phenylamino-thiazolo[5,4-d]pyrimidines as Novel Non-Nucleoside Partial Agonists for the A(2A) Adenosine Receptor: Prediction from Molecular Modeling2016In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 59, no 12, p. 5922-5928Article in journal (Refereed)
    Abstract [en]

    We describe the identification of 7-(prolinol-N-yl)-2-phenylamino-thiazolo[5,4-d]pyrimidines as a novel chemotype of non-nucleoside partial agonists for the A(2A) adenosine receptor (A(2A)AR). Molecular-modeling indicated that the (S)-2-hydroxymethylene-pyrrolidine could mimic the interactions of agonists' ribose, suggesting that this class of compounds could have agonistic properties. This was confirmed by functional assays on the A(2A)AR, where their efficacy could be associated with the presence of the 2-hydroxymethylene moiety. Additionally, the best compound displays promising affinity, selectivity profile, and physicochemical properties.

  • 16.
    Björneholm, Olle
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Molecular and condensed matter physics.
    Hansen, Martin H.
    Tech Univ Denmark, DK-2800 Lyngby, Denmark.;Univ Copenhagen, Dept Chem, Univ Pk 5, DK-2100 Copenhagen, Denmark..
    Hodgson, Andrew
    Univ Liverpool, Dept Chem, Liverpool L69 7ZD, Merseyside, England..
    Liu, Li-Min
    UCL, London Ctr Nanotechnol, Thomas Young Ctr, Dept Phys & Astron, London WC1E 6BT, England.;UCL, Dept Chem, London WC1E 6BT, England.;Beijing Computat Sci Res Ctr, Beijing 100193, Peoples R China..
    Limmer, David T.
    Princeton Univ, Princeton Ctr Theoret Sci, Princeton, NJ 08544 USA..
    Michaelides, Angelos
    UCL, London Ctr Nanotechnol, Thomas Young Ctr, Dept Phys & Astron, London WC1E 6BT, England.;UCL, Dept Chem, London WC1E 6BT, England..
    Pedevilla, Philipp
    UCL, London Ctr Nanotechnol, Thomas Young Ctr, Dept Phys & Astron, London WC1E 6BT, England.;UCL, Dept Chem, London WC1E 6BT, England..
    Rossmeisl, Jan
    Univ Copenhagen, Dept Chem, Univ Pk 5, DK-2100 Copenhagen, Denmark..
    Shen, Huaze
    Peking Univ, Int Ctr Quantum Mat, Beijing 100871, Peoples R China.;Peking Univ, Sch Phys, Beijing 100871, Peoples R China..
    Tocci, Gabriele
    UCL, London Ctr Nanotechnol, Thomas Young Ctr, Dept Phys & Astron, London WC1E 6BT, England.;UCL, Dept Chem, London WC1E 6BT, England.;Ecole Polytech Fed Lausanne, Sch Engn, Inst Bioengn & Mat Sci & Engn, Lab Fundamental BioPhoton,Lab Computat Sci & Mode, CH-1015 Lausanne, Switzerland.;Ecole Polytech Fed Lausanne, Lausanne Ctr Ultrafast Sci, CH-1015 Lausanne, Switzerland..
    Tyrode, Eric
    KTH Royal Inst Technol, Dept Chem, S-10044 Stockholm, Sweden..
    Walz, Marie-Madeleine
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Molecular and condensed matter physics. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Werner, Josephina
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Molecular and condensed matter physics. Swedish Univ Agr Sci, Dept Chem & Biotechnol, Box 7015, S-75007 Uppsala, Sweden..
    Bluhm, Hendrik
    Lawrence Berkeley Natl Lab, Div Chem Sci, Berkeley, CA 94720 USA..
    Water at Interfaces2016In: Chemical Reviews, ISSN 0009-2665, E-ISSN 1520-6890, Vol. 116, no 13, p. 7698-7726Article, review/survey (Refereed)
    Abstract [en]

    The interfaces of neat water and aqueous solutions play a prominent role in many technological processes and in the environment. Examples of aqueous interfaces are ultrathin water films that cover most hydrophilic surfaces under ambient relative humidities, the liquid/solid interface which drives many electrochemical reactions, and the liquid/vapor interface, which governs the uptake and release of trace gases by the oceans and cloud droplets. In this article we review some of the recent experimental and theoretical advances in our knowledge of the properties of aqueous interfaces and discuss open questions and gaps in our understanding.

  • 17.
    Borroto-Escuela, Dasiel O.
    et al.
    Karolinska Inst, Dept Neurosci, Retzius Vag 8, S-17177 Stockholm, Sweden;Univ Urbino Carlo Bo, Dept Biomol Sci, I-61029 Urbino, Italy;Observ Cubano Neurociencias, Grp Bohio Estudio, Zaya 50, Yaguajay 62100, Cuba.
    Narvaez, Manuel
    Univ Malaga, Inst Invest Biomed Malaga, Fac Med, E-29071 Malaga, Spain.
    Ambrogini, Patrizia
    Univ Urbino Carlo Bo, Dept Biomol Sci, I-61029 Urbino, Italy.
    Ferraro, Luca
    Univ Ferrara, SVEB, Dept Life Sci & Biotechnol, I-44121 Ferrara, Italy.
    Brito, Ismel
    Karolinska Inst, Dept Neurosci, Retzius Vag 8, S-17177 Stockholm, Sweden;Observ Cubano Neurociencias, Grp Bohio Estudio, Zaya 50, Yaguajay 62100, Cuba.
    Romero Fernandez, Wilber
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Andrade-Talavera, Yuniesky
    Karolinska Inst, Dept Neurobiol Care Sci & Soc, Ctr Alzheimer Res, Neuronal Oscillat Lab, S-17177 Stockholm, Sweden.
    Flores-Burgess, Antonio
    Univ Malaga, Inst Invest Biomed Malaga, Fac Med, E-29071 Malaga, Spain.
    Millon, Carmelo
    Univ Malaga, Inst Invest Biomed Malaga, Fac Med, E-29071 Malaga, Spain.
    Gago, Belen
    Univ Malaga, Inst Invest Biomed Malaga, Fac Med, E-29071 Malaga, Spain.
    Angel Narvaez, Jose
    Univ Malaga, Inst Invest Biomed Malaga, Fac Med, E-29071 Malaga, Spain.
    Odagaki, Yuji
    Saitama Med Univ, Dept Psychiat, Saitama 3388570, Japan.
    Palkovits, Miklos
    Semmelweis Univ, Fac Med, Dept Anat Histol & Embryol, H-1094 Budapest, Hungary.
    Diaz-Cabiale, Zaida
    Univ Malaga, Inst Invest Biomed Malaga, Fac Med, E-29071 Malaga, Spain.
    Fuxe, Kjell
    Karolinska Inst, Dept Neurosci, Retzius Vag 8, S-17177 Stockholm, Sweden.
    Receptor-Receptor Interactions in Multiple 5-HT1A Heteroreceptor Complexes in Raphe-Hippocampal 5-HT Transmission and Their Relevance for Depression and Its Treatment2018In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 23, no 6, article id 1341Article, review/survey (Refereed)
    Abstract [en]

    Due to the binding to a number of proteins to the receptor protomers in receptor heteromers in the brain, the term "heteroreceptor complexes" was introduced. A number of serotonin 5-HT1A heteroreceptor complexes were recently found to be linked to the ascending 5-HT pathways known to have a significant role in depression. The 5-HT1A-FGFR1 heteroreceptor complexes were involved in synergistically enhancing neuroplasticity in the hippocampus and in the dorsal raphe 5-HT nerve cells. The 5-HT1A protomer significantly increased FGFR1 protomer signaling in wild-type rats. Disturbances in the 5-HT1A-FGFR1 heteroreceptor complexes in the raphe-hippocampal 5-HT system were found in a genetic rat model of depression (Flinders sensitive line (FSL) rats). Deficits in FSL rats were observed in the ability of combined FGFR1 and 5-HT1A agonist cotreatment to produce antidepressant-like effects. It may in part reflect a failure of FGFR1 treatment to uncouple the 5-HT1A postjunctional receptors and autoreceptors from the hippocampal and dorsal raphe GIRK channels, respectively. This may result in maintained inhibition of hippocampal pyramidal nerve cell and dorsal raphe 5-HT nerve cell firing. Also, 5-HT1A-5-HT2A isoreceptor complexes were recently demonstrated to exist in the hippocampus and limbic cortex. They may play a role in depression through an ability of 5-HT2A protomer signaling to inhibit the 5-HT1A protomer recognition and signaling. Finally, galanin (1-15) was reported to enhance the antidepressant effects of fluoxetine through the putative formation of GalR1-GalR2-5-HT1A heteroreceptor complexes. Taken together, these novel 5-HT1A receptor complexes offer new targets for treatment of depression.

  • 18.
    Borroto-Escuela, Dasiel O.
    et al.
    Karolinska Inst, Dept Neurosci, Stockholm, Sweden.
    Rodriguez, David
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Stockholm, Sweden.
    Romero Fernandez, Wilber
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kapla, Jon
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Jaiteh, Mariama
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ranganathan, Anirudh
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Stockholm, Sweden.
    Lazarova, Tzvetana
    Autonomous Univ Barcelona, Fac Med, Dept Biochem & Mol Biol, Inst Neurosci, Barcelona, Spain.
    Fuxe, Kjell
    Karolinska Inst, Dept Neurosci, Stockholm, Sweden.
    Carlsson, Jens
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Mapping the Interface of a GPCR Dimer: A Structural Model of the A(2A) Adenosine and D-2 Dopamine Receptor Heteromer2018In: Frontiers in Pharmacology, ISSN 1663-9812, E-ISSN 1663-9812, Vol. 9, article id 829Article in journal (Refereed)
    Abstract [en]

    The A(2A) adenosine (A(2A)R) and D-2 dopamine (D2R) receptors form oligomers in the cell membrane and allosteric interactions across the A(2A)R-D2R heteromer represent a target for development of drugs against central nervous system disorders. However, understanding of the molecular determinants of A(2A)R-D2R heteromerization and the allosteric antagonistic interactions between the receptor protomers is still limited. In this work, a structural model of the A(2A)R-D2R heterodimer was generated using a combined experimental and computational approach. Regions involved in the heteromer interface were modeled based on the effects of peptides derived from the transmembrane (TM) helices on A(2A)R-D2R receptor-receptor interactions in bioluminescence resonance energy transfer (BRET) and proximity ligation assays. Peptides corresponding to TM-IV and TM-V of the A(2A)R blocked heterodimer interactions and disrupted the allosteric effect of A(2A)R activation on D2R agonist binding. Protein-protein docking was used to construct a model of the A(2A)R-D2R heterodimer with a TM-IV/V interface, which was refined using molecular dynamics simulations. Mutations in the predicted interface reduced A(2A)R-D2R interactions in BRET experiments and altered the allosteric modulation. The heterodimer model provided insights into the structural basis of allosteric modulation and the technique developed to characterize the A(2A)R-D2R interface can be extended to study the many other G protein-coupled receptors that engage in heteroreceptor complexes.

  • 19.
    Bálint, Mónika
    et al.
    University of Pécs, Medical School, Department of Pharmacology and Pharmacotherapy; Eötvös Loránd University, Department of Biochemistry.
    Jeszenői, Norbert
    University of Pécs, Center for Neuroscience, MTA NAP -B Molecular Neuroendocrinology Group, Institute of Physiology.
    Horváth, István
    University of Szeged, Chemistry Doctoral School.
    van der Spoel, David
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Hetényi, Csaba
    University of Pécs, Medical School, Department of Pharmacology and Pharmacotherapy.
    Systematic exploration of multiple drug binding sites2017In: Journal of Cheminformatics, ISSN 1758-2946, E-ISSN 1758-2946, Vol. 9, no 65Article in journal (Refereed)
    Abstract [en]

    Background: Targets with multiple (prerequisite or allosteric) binding sites have an increasing importance in drug design. Experimental determination of atomic resolution structures of ligands weakly bound to multiple binding sites is often challenging. Blind docking has been widely used for fast mapping of the entire target surface for multiple binding sites. Reliability of blind docking is limited by approximations of hydration models, simplified handling of molecular flexibility, and imperfect search algorithms.

    Results: To overcome such limitations, the present study introduces Wrap 'n' Shake (WnS), an atomic resolution method that systematically "wraps" the entire target into a monolayer of ligand molecules. Functional binding sites are extracted by a rapid molecular dynamics shaker. WnS is tested on biologically important systems such as mitogenactivated protein, tyrosine-protein kinases, key players of cellular signaling, and farnesyl pyrophosphate synthase, a target of antitumor agents.

  • 20.
    Carbajales, Carlos
    et al.
    Univ Santiago de Compostela, Fac Farm, Ctr Singular Invest Quim Biol & Mat Mol CIQUS, Santiago De Compostela 15782, Spain.;Univ Santiago de Compostela, Fac Farm, Dept Quim Organ, Santiago De Compostela 15782, Spain..
    Azuaje, Jhonny
    Univ Santiago de Compostela, Fac Farm, Ctr Singular Invest Quim Biol & Mat Mol CIQUS, Santiago De Compostela 15782, Spain.;Univ Santiago de Compostela, Fac Farm, Dept Quim Organ, Santiago De Compostela 15782, Spain..
    Oliveira, Ana
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Loza, Maria I.
    Univ Santiago de Compostela, Drug Screening Platform Biofarma Res Grp, Ctr Singular Invest Med Mol & Enfermedades Cron C, Santiago De Compostela 15782, Spain..
    Brea, Jose
    Univ Santiago de Compostela, Drug Screening Platform Biofarma Res Grp, Ctr Singular Invest Med Mol & Enfermedades Cron C, Santiago De Compostela 15782, Spain..
    Cadavid, Maria I.
    Univ Santiago de Compostela, Drug Screening Platform Biofarma Res Grp, Ctr Singular Invest Med Mol & Enfermedades Cron C, Santiago De Compostela 15782, Spain..
    Masaguer, Christian F.
    Univ Santiago de Compostela, Fac Farm, Dept Quim Organ, Santiago De Compostela 15782, Spain..
    Garcia-Mera, Xerardo
    Univ Santiago de Compostela, Fac Farm, Dept Quim Organ, Santiago De Compostela 15782, Spain..
    Gutiérrez-de-Terán, Hugo
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Sotelo, Eddy
    Univ Santiago de Compostela, Fac Farm, Ctr Singular Invest Quim Biol & Mat Mol CIQUS, Santiago De Compostela 15782, Spain.;Univ Santiago de Compostela, Fac Farm, Dept Quim Organ, Santiago De Compostela 15782, Spain..
    Enantiospecific Recognition at the A(2B) Adenosine Receptor by Alkyl 2-Cyanoimino-4-substituted-6-methyl-1,2,3,4-tetrahydropyrimidine-5-carboxylates2017In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 60, no 8, p. 3372-3382Article in journal (Refereed)
    Abstract [en]

    A novel family of structurally simple, potent, and selective nonxanthine A(2B)AR ligands was identified, and its antagonistic behavior confirmed through functional experiments. The reported alkyl 2-cyanoimino-4-substituted-6-methyl-1,2,3,4-tetrahy-dropyrimidine-5-carboxylates (16) were designed by bioisosteric replacement of the carbonyl group at position 2 in a series of 3,4-dihydropyrimidin-2-ones. The scaffold (16) documented herein contains a chiral center at the heterocycle. Accordingly, the most attractive ligand of the series [(+/-)16b, K-i = 24.3 nM] was resolved into its two enantiomers by chiral HPLC, and the absolute configuration was established by circular dichroism. The biological evaluation of both enantiomers demonstrated enantiospecific recognition at A(2B)AR, with the (S)-16b enantiomer retaining all the affinity (K-i = 15.1 nM), as predicted earlier by molecular modeling. This constitutes the first example of enantiospecific recognition at the A(2B) adenosine receptor and opens new possibilities in ligand design for this receptor.

  • 21.
    Carlsson, Jens
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Structure-based screening for GPCR ligands from fragment and lead-like chemical space2018In: Abstract of Papers of the American Chemical Society, ISSN 0065-7727, Vol. 255Article in journal (Other academic)
  • 22.
    Crespo, Abel
    et al.
    Univ Santiago de Compostela, Ctr Singular Invest Quim Biol & Mat Mol CIQUS, Santiago De Compostela 1578, Spain.;Univ Santiago de Compostela, Fac Farm, Dept Quim Organ, Santiago De Compostela 1578, Spain..
    El Maatougui, Abdelaziz
    Univ Santiago de Compostela, Ctr Singular Invest Quim Biol & Mat Mol CIQUS, Santiago De Compostela 1578, Spain.;Univ Santiago de Compostela, Fac Farm, Dept Quim Organ, Santiago De Compostela 1578, Spain..
    Azuaje, Jhonny
    Univ Santiago de Compostela, Ctr Singular Invest Quim Biol & Mat Mol CIQUS, Santiago De Compostela 1578, Spain.;Univ Santiago de Compostela, Fac Farm, Dept Quim Organ, Santiago De Compostela 1578, Spain..
    Escalante, Luz
    Univ Santiago de Compostela, Ctr Singular Invest Quim Biol & Mat Mol CIQUS, Santiago De Compostela 1578, Spain.;Univ Santiago de Compostela, Fac Farm, Dept Quim Organ, Santiago De Compostela 1578, Spain..
    Majellaro, Maria
    Univ Santiago de Compostela, Ctr Singular Invest Quim Biol & Mat Mol CIQUS, Santiago De Compostela 1578, Spain.;Univ Santiago de Compostela, Fac Farm, Dept Quim Organ, Santiago De Compostela 1578, Spain..
    Loza, Maria Isabel
    Univ Santiago de Compostela, Ctr Singular Invest Med Mol & Enfermedades Cron C, Santiago De Compostela 1578, Spain..
    Brea, Jose
    Univ Santiago de Compostela, Ctr Singular Invest Med Mol & Enfermedades Cron C, Santiago De Compostela 1578, Spain..
    Isabel Cadavid, Mara
    Univ Santiago de Compostela, Ctr Singular Invest Med Mol & Enfermedades Cron C, Santiago De Compostela 1578, Spain..
    Gutiérrez-de-Terán, Hugo
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Sotelo, Eddy
    Univ Santiago de Compostela, Ctr Singular Invest Quim Biol & Mat Mol CIQUS, Santiago De Compostela 1578, Spain.;Univ Santiago de Compostela, Fac Farm, Dept Quim Organ, Santiago De Compostela 1578, Spain..
    Exploring the influence of the substituent at position 4 in a series of 3,4-dihydropyrimidin-2(1H)-one A(2B) adenosine receptor antagonists2017In: Chemistry of Heterocyclic Compounds, ISSN 0009-3122, E-ISSN 1573-8353, Vol. 53, no 3, p. 316-321Article in journal (Refereed)
    Abstract [en]

    In the context of a program to identify selective adenosine A(2B) receptor antagonists, we have obtained a focused library of 4-substituted 3,4-dihydropyrimidin-2(1H)-ones and its affinity for the four human adenosine receptor subtypes was determined. The synthesis was accomplished by using an experimentally simple and efficient Biginelli approach. The biological evaluation of the library revealed that all the documented derivatives exhibit low or negligible affinity for the A(2B) receptor, thus highlighting the critical importance of the substituent at position 4 of the 3,4-dihydropyrimidin-2(1H)-one chemotype.

  • 23.
    Dabrowski, Michal J.
    et al.
    Polish Acad Sci, Inst Comp Sci, Warsaw, Poland..
    Draminski, Michal
    Polish Acad Sci, Inst Comp Sci, Warsaw, Poland..
    Diamanti, Klev
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Stepniak, Karolina
    Nencki Inst Expt Biol, Warsaw, Poland..
    Mozolewska, Magdalena A.
    Polish Acad Sci, Inst Comp Sci, Warsaw, Poland..
    Teisseyre, Pawel
    Polish Acad Sci, Inst Comp Sci, Warsaw, Poland..
    Koronacki, Jacek
    Polish Acad Sci, Inst Comp Sci, Warsaw, Poland..
    Komorowski, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Polish Acad Sci, Inst Comp Sci, Warsaw, Poland.
    Kaminska, Bozena
    Nencki Inst Expt Biol, Warsaw, Poland..
    Wojtas, Bartosz
    Nencki Inst Expt Biol, Warsaw, Poland..
    Unveiling new interdependencies between significant DNA methylation sites, gene expression profiles and glioma patients survival2018In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 8, article id 4390Article in journal (Refereed)
    Abstract [en]

    In order to find clinically useful prognostic markers for glioma patients' survival, we employed Monte Carlo Feature Selection and Interdependencies Discovery (MCFS-ID) algorithm on DNA methylation (HumanMethylation450 platform) and RNA-seq datasets from The Cancer Genome Atlas (TCGA) for 88 patients observed until death. The input features were ranked according to their importance in predicting patients' longer (400+ days) or shorter (<= 400 days) survival without prior classification of the patients. Interestingly, out of the 65 most important features found, 63 are methylation sites, and only two mRNAs. Moreover, 61 out of the 63 methylation sites are among those detected by the 450 k array technology, while being absent in the HumanMethylation27. The most important methylation feature (cg15072976) overlaps with the RE1 Silencing Transcription Factor (REST) binding site, and was confirmed to intersect with the REST binding motif in human U87 glioma cells. Six additional methylation sites from the top 63 overlap with REST sites. We found that the methylation status of the cg15072976 site affects transcription factor binding in U87 cells in gel shift assay. The cg15072976 methylation status discriminates <= 400 and 400+ patients in an independent dataset from TCGA and shows positive association with survival time as evidenced by Kaplan-Meier plots.

  • 24.
    de Teran, Hugo Gutierrez
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Understanding ligand binding and receptor selectivity through molecular simulations2015In: European Biophysics Journal, ISSN 0175-7571, E-ISSN 1432-1017, Vol. 44, p. S202-S202Article in journal (Other academic)
  • 25.
    Diamanti, Klev
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Umer, Husen M.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Kruczyk, Marcin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Dabrowski, Michal J.
    Polish Acad Sci, Inst Comp Sci, PL-01248 Warsaw, Poland..
    Cavalli, Marco
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Wadelius, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Komorowski, Jan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Polish Acad Sci, Inst Comp Sci, PL-01248 Warsaw, Poland..
    Maps of context-dependent putative regulatory regions and genomic signal interactions2016In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 44, no 19, p. 9110-9120Article in journal (Refereed)
    Abstract [en]

    Gene transcription is regulated mainly by transcription factors (TFs). ENCODE and Roadmap Epigenomics provide global binding profiles of TFs, which can be used to identify regulatory regions. To this end we implemented a method to systematically construct cell-type and species-specific maps of regulatory regions and TF-TF interactions. We illustrated the approach by developing maps for five human cell-lines and two other species. We detected similar to 144k putative regulatory regions among the human cell-lines, with the majority of them being similar to 300 bp. We found similar to 20k putative regulatory elements in the ENCODE heterochromatic domains suggesting a large regulatory potential in the regions presumed transcriptionally silent. Among the most significant TF interactions identified in the heterochromatic regions were CTCF and the cohesin complex, which is in agreement with previous reports. Finally, we investigated the enrichment of the obtained putative regulatory regions in the 3D chromatin domains. More than 90% of the regions were discovered in the 3D contacting domains. We found a significant enrichment of GWAS SNPs in the putative regulatory regions. These significant enrichments provide evidence that the regulatory regions play a crucial role in the genomic structural stability. Additionally, we generated maps of putative regulatory regions for prostate and colorectal cancer human cell-lines.

  • 26.
    Diwakarla, Shanti
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Nylander, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Grönbladh, Alfhild
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Vanga, Sudarsana Reddy
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Khan, Yasmin Shamsudin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Gutierrez-de-Teran, Hugo
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Sävmarker, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Ng, Leelee
    Monash Univ, Dept Physiol, Biomed Discovery Inst, Clayton, Vic 3800, Australia..
    Pham, Vi
    Biomedicine Discovery Institute, Department of Physiology, Monash University, Clayton, Victoria 3800, Australia.
    Lundback, Thomas
    Karolinska Inst, Chem Biol Consortium Sweden, Sci Life Lab, Div Translat Med & Chem Biol,Dept Med Biochem & B, S-17177 Solna, Sweden..
    Jenmalm-Jensen, Annika
    Karolinska Inst, Chem Biol Consortium Sweden, Sci Life Lab, Div Translat Med & Chem Biol,Dept Med Biochem & B, S-17177 Solna, Sweden..
    Svensson, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Zelleroth, Sofia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Engen, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Rosenström, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
    Larhed, Mats
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Division of Molecular Imaging.
    Åqvist, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Chai, Siew Yeen
    Biomedicine Discovery Institute, Department of Physiology, Monash University, Clayton, Victoria 3800, Australia.
    Hallberg, Mathias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Aryl Sulfonamide Inhibitors of Insulin-Regulated Aminopeptidase Enhance Spine Density in Primary Hippocampal Neuron Cultures2016In: ACS Chemical Neuroscience, ISSN 1948-7193, E-ISSN 1948-7193, Vol. 7, no 10, p. 1383-1392Article in journal (Refereed)
    Abstract [en]

    The zinc metallopeptidase insulin regulated aminopeptidase (IRAP), which is highly expressed in the hippocampus and other brain regions associated with cognitive function, has been identified as a high-affinity binding site of the hexapeptide angiotensin IV (Ang IV). This hexapeptide is thought to facilitate learning and memory by binding to the catalytic site of IRAP to inhibit its enzymatic activity. In support of this hypothesis, low molecular weight, nonpeptide specific inhibitors of TRAP have been shown to enhance memory in rodent models. Recently, it was demonstrated that linear and macrocyclic Ang IV-derived peptides can alter the shape and increase the number of dendritic spines in hippocampal cultures, properties associated with enhanced cognitive performance. After screening a library of 10 500 drug like substances for their ability to inhibit IRAP, we identified a series of low molecular weight aryl sulfonamides, which exhibit no structural similarity to Ang IV, as moderately potent IRAP inhibitors:A structural and biological characterization of three of these aryl sulfonamides was performed. Their binding modes to human IRAP were explored by docking calculations combined with molecular dynamics simulations and binding affinity estimations using the linear interaction energy method. Two alternative binding modes emerged from this analysis, both of which correctly rank the ligands according to their experimental binding affinities for this series of compounds. Finally, we show that two of these drug-like IRAP inhibitors can alter dendritic spine morphology and increase spine density in primary cultures of hippocampal neurons.

  • 27.
    dos Santos Soares, Ricardo de Oliveira
    et al.
    Fac Med Marilia, Marilia, Brazil..
    Bortot, Leandro Oliveira
    Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, Dept Fis & Quim, Grp Fis Biol, Ribeirao Preto, Brazil..
    van Der Spoel, David
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Caliri, Antonio
    Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, Dept Fis & Quim, Grp Fis Biol, Ribeirao Preto, Brazil..
    Membrane vesiculation induced by proteins of the dengue virus envelope studied by molecular dynamics simulations2017In: Journal of Physics: Condensed Matter, ISSN 0953-8984, E-ISSN 1361-648X, Vol. 29, no 50, article id 504002Article in journal (Refereed)
    Abstract [en]

    Biological membranes are continuously remodeled in the cell by specific membrane-shaping machineries to form, for example, tubes and vesicles. We examine fundamental mechanisms involved in the vesiculation processes induced by a cluster of envelope (E) and membrane (M) proteins of the dengue virus (DENV) using molecular dynamics simulations and a coarse-grained model. We show that an arrangement of three E-M heterotetramers (EM3) works as a bending unit and an ordered cluster of five such units generates a closed vesicle, reminiscent of the virus budding process. In silico mutagenesis of two charged residues of the anchor helices of the envelope proteins of DENV shows that Arg-471 and Arg-60 are fundamental to produce bending stress on the membrane. The fine-tuning between the size of the EM3 unit and its specific bending action suggests this protein unit is an important factor in determining the viral particle size.

  • 28.
    Dourado, Daniel F. A. R.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Flores, Samuel Coulbourn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Modeling and fitting protein-protein complexes to predict change of binding energy2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 25406Article in journal (Refereed)
    Abstract [en]

    It is possible to accurately and economically predict change in protein-protein interaction energy upon mutation (Delta Delta G), when a high-resolution structure of the complex is available. This is of growing usefulness for design of high-affinity or otherwise modified binding proteins for therapeutic, diagnostic, industrial, and basic science applications. Recently the field has begun to pursue Delta Delta G prediction for homology modeled complexes, but so far this has worked mostly for cases of high sequence identity. If the interacting proteins have been crystallized in free (uncomplexed) form, in a majority of cases it is possible to find a structurally similar complex which can be used as the basis for template-based modeling. We describe how to use MMB to create such models, and then use them to predict Delta Delta G, using a dataset consisting of free target structures, co-crystallized template complexes with sequence identify with respect to the targets as low as 44%, and experimental Delta Delta G measurements. We obtain similar results by fitting to a low-resolution Cryo-EM density map. Results suggest that other structural constraints may lead to a similar outcome, making the method even more broadly applicable.

  • 29. Dramiński, Michał
    et al.
    Da̧browski, Michał J.
    Diamanti, Klev
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Koronacki, Jacek
    Komorowski, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Discovering Networks of Interdependent Features in High-Dimensional Problems2016In: Big Data Analysis: New Algorithms for a New Society / [ed] Japkowicz, Nathalie; Stefanowski, Jerzy, Cham: Springer, 2016, p. 285-304Chapter in book (Refereed)
    Abstract [en]

    The availability of very large data sets in Life Sciences provided earlier by the technological breakthroughs such as microarrays and more recently by various forms of sequencing has created both challenges in analyzing these data as well as new opportunities. A promising, yet underdeveloped approach to Big Data, not limited to Life Sciences, is the use of feature selection and classification to discover interdependent features. Traditionally, classifiers have been developed for the best quality of supervised classification. In our experience, more often than not, rather than obtaining the best possible supervised classifier, the Life Scientist needs to know which features contribute best to classifying observations (objects, samples) into distinct classes and what the interdependencies between the features that describe the observation. Our underlying hypothesis is that the interdependent features and rule networks do not only reflect some syntactical properties of the data and classifiers but also may convey meaningful clues about true interactions in the modeled biological system. In this chapter we develop further our method of Monte Carlo Feature Selection and Interdependency Discovery (MCFS and MCFS-ID, respectively), which are particularly well suited for high-dimensional problems, i.e., those where each observation is described by very many features, often many more features than the number of observations. Such problems are abundant in Life Science applications. Specifically, we define Inter-Dependency Graphs (termed, somewhat confusingly, ID Graphs) that are directed graphs of interactions between features extracted by aggregation of information from the classification trees constructed by the MCFS algorithm. We then proceed with modeling interactions on a finer level with rule networks. We discuss some of the properties of the ID graphs and make a first attempt at validating our hypothesis on a large gene expression data set for CD4+ T-cells. The MCFS-ID and ROSETTA including the Ciruvis approach offer a new methodology for analyzing Big Data from feature selection, through identification of feature interdependencies, to classification with rules according to decision classes, to construction of rule networks. Our preliminary results confirm that MCFS-ID is applicable to the identification of interacting features that are functionally relevant while rule networks offer a complementary picture with finer resolution of the interdependencies on the level of feature-value pairs.

  • 30.
    Duarte, Fernanda
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab. Univ Oxford, Chem Res Lab, 12 Mansfield Rd, Oxford OX1 3TA, England.;Univ Oxford, Phys & Theoret Chem Lab, S Parks Rd, Oxford OX1 3QZ, England..
    Barrozo, Alexandre
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Åqvist, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Williams, Nicholas H.
    Univ Sheffield, Dept Chem, Sheffield S3 7HF, S Yorkshire, England..
    Kamerlin, Shina C. Lynn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    The Competing Mechanisms of Phosphate Monoester Dianion Hydrolysis2016In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 138, no 33, p. 10664-10673Article in journal (Refereed)
    Abstract [en]

    Despite the numerous experimental and theoretical studies on phosphate monoester hydrolysis, significant questions remain concerning the mechanistic details of these biologically critical reactions. In the present work we construct a linear free energy relationship for phosphate monoester hydrolysis to explore the effect of modulating leaving group plc on the competition between solvent- and substrate-assisted pathways for the hydrolysis of these compounds. Through detailed comparative electronic-structure studies of methyl phosphate and a series of substituted aryl phosphate monoesters, we demonstrate that the preferred mechanism is dependent on the nature of the leaving group. For good leaving groups, a strong preference is observed for a more dissociative solvent-assisted pathway. However, the energy difference between the two pathways gradually reduces as the leaving group pK(a) increases and creates mechanistic ambiguity for reactions involving relatively poor alkoxy leaving groups. Our calculations show that the transition-state structures vary smoothly across the range of pK(a)s studied and that the pathways remain discrete mechanistic alternatives. Therefore, while not impossible, a biological catalyst would have to surmount a significantly higher activation barrier to facilitate a substrate-assisted pathway than for the solvent-assisted pathway when phosphate is bonded to good leaving groups. For poor leaving groups, this intrinsic preference disappears.

  • 31.
    Ekholm, Victor
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Molecular and Condensed Matter Physics.
    Caleman, C
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular biophysics. Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Molecular and Condensed Matter Physics.
    Walz, Marie-Madeleine
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Molecular and Condensed Matter Physics. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Werner, Josephina
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Molecular and Condensed Matter Physics.
    Öhrwall, Gunnar
    Rubensson, Jan-Erik
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Molecular and Condensed Matter Physics.
    Björneholm, Olle
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Molecular and Condensed Matter Physics.
    Surface propensity of atmospherically relevant carboxylates and alkyl ammonium ions studied by XPS: towards a building-block model of surface propensity based on Langmuir adsorptionManuscript (preprint) (Other academic)
  • 32.
    Ekholm, Victor
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Molecular and Condensed Matter Physics.
    Caleman, Carl
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular biophysics. Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Molecular and Condensed Matter Physics.
    Bjärnhall Prytz, Nicklas
    Walz, Marie-Madeleine
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Werner, Josephina
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Molecular and Condensed Matter Physics.
    Öhrwall, Gunnar
    Rubensson, Jan-Erik
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Molecular and Condensed Matter Physics. Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Nanotechnology and Functional Materials.
    Björneholm, Olle
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Molecular and Condensed Matter Physics.
    Strong Enrichment of Atmospherically Relevant Organic Ions at the Aqueous Interface: The Role of Ion Pairing and Cooperative EffectsIn: Article in journal (Other academic)
  • 33.
    Ekholm, Victor
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Molecular and Condensed Matter Physics. Uppsala Univ, Dept Phys & Astron, POB 516, SE-75120 Uppsala, Sweden.
    Vazdar, Mario
    Rudjer Boskovic Inst, Bijenicka Cesta 54, Zagreb 10000, Croatia.
    Mason, Philip E.
    Acad Sci Czech Republ, Inst Organ Chem & Biochem, Flemingovo Nam 2, CR-16610 Prague 6, Czech Republic.
    Bialik, Erik
    Lund Univ, Dept Chem, Phys Chem, POB 124, SE-22100 Lund, Sweden.
    Walz, Marie-Madeleine
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Uppsala Univ, Dept Cell & Mol Biol Computat Biol & Bioinformat, POB 596, SE-75124 Uppsala, Sweden.
    Ohrwall, Gunnar
    Lund Univ, MAX Lab 4, POB 118, SE-22100 Lund, Sweden.
    Werner, Josephina
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Molecular and Condensed Matter Physics.
    Rubensson, Jan-Erik
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Molecular and Condensed Matter Physics.
    Jungwirth, Pavel
    Acad Sci Czech Republ, Inst Organ Chem & Biochem, Flemingovo Nam 2, CR-16610 Prague 6, Czech Republic.
    Björneholm, Olle
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics and Astronomy, Molecular and Condensed Matter Physics.
    Anomalous surface behavior of hydrated guanidinium ions due to ion pairing2018In: Journal of Chemical Physics, ISSN 0021-9606, E-ISSN 1089-7690, Vol. 148, no 14, article id 144508Article in journal (Refereed)
    Abstract [en]

    Surface affinity of aqueous guanidinium chloride (GdmCl) is compared to that of aqueous tetrapropylammonium chloride (TPACl) upon addition of sodium chloride (NaCl) or disodium sulfate (Na2SO4). The experimental results have been acquired using the surface sensitive technique X-ray photoelectron spectroscopy on a liquid jet. Molecular dynamics simulations have been used to produce radial distribution functions and surface density plots. The surface affinities of both TPA(+) and Gdm(+) increase upon adding NaCl to the solution. With the addition of Na2SO4, the surface affinity of TPA(+) increases, while that of Gdm(+) decreases. From the results of MD simulations it is seen that Gdm(+) and SO42- ions form pairs. This finding can be used to explain the decreased surface affinity of Gdm(+) when co-dissolved with SO42- ions. Since SO42- ions avoid the surface due to the double charge and strong water interaction, the Gdm(+)-SO42- ion pair resides deeper in the solutions' bulk than the Gdm(+) ions. Since TPA(+) does not form ion pairs with SO42-, the TPA(+) ions are instead enriched at the surface.

  • 34.
    El Maatougui, Abdelaziz
    et al.
    Univ Santiago de Compostela, Ctr Singular Invest Quim Biol & Mat Mol CIQUS, Santiago De Compostela 15782, Spain..
    Yanez, Matilde
    Univ Santiago de Compostela, Fac Farm, Dept Farmacol, Santiago De Compostela 15782, Spain..
    Crespo, Abel
    Univ Santiago de Compostela, Ctr Singular Invest Quim Biol & Mat Mol CIQUS, Santiago De Compostela 15782, Spain..
    Fraiz, Nuria
    Univ Santiago de Compostela, Fac Farm, Dept Farmacol, Santiago De Compostela 15782, Spain..
    Coelho, Alberto
    Univ Santiago de Compostela, Fac Farm, Dept Quim Organ, Santiago De Compostela 15782, Spain..
    Ravina, Enrique
    Univ Santiago de Compostela, Fac Farm, Dept Quim Organ, Santiago De Compostela 15782, Spain..
    Laguna, Reyes
    Univ Santiago de Compostela, Fac Farm, Dept Farmacol, Santiago De Compostela 15782, Spain..
    Cano, Ernesto
    Univ Santiago de Compostela, Fac Farm, Dept Farmacol, Santiago De Compostela 15782, Spain..
    Loza, Maria I.
    Univ Santiago de Compostela, Fac Farm, Dept Farmacol, Santiago De Compostela 15782, Spain.;Univ Santiago de Compostela, Ctr Singular Invest Med Mol & Enfermedades, Santiago De Compostela 15782, Spain..
    Brea, Jose
    Univ Santiago de Compostela, Ctr Singular Invest Med Mol & Enfermedades, Santiago De Compostela 15782, Spain..
    Gutiérrez de Terán, Hugo
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Sotelo, Eddy
    Univ Santiago de Compostela, Ctr Singular Invest Quim Biol & Mat Mol CIQUS, Santiago De Compostela 15782, Spain.;Univ Santiago de Compostela, Fac Farm, Dept Quim Organ, Santiago De Compostela 15782, Spain..
    3-Oxopyridazin-5-yl-Chalcone Hybrids: Potent Antiplatelet Agents That Prevent Glycoprotein IIb/IIIa Activation2017In: CHEMISTRYSELECT, ISSN 2365-6549, Vol. 2, no 17, p. 4920-4933Article in journal (Refereed)
    Abstract [en]

    A novel family of potent and broad-spectrum antiplatelet agents has been discovered by exploration of a library of 3-oxopyridazin-5-yl-chalcone hybrids. The pharmacological evaluation of the collection established the most salient features of the SAR in this series and allowed the identification of lead compounds that exhibit antiplatelet activity that is substantially superior to drugs in clinical use and 3,4-methylenedioxy-β-nitrostyrene (MNS). The derivatives reported herein act on GPIIb/IIIa, but in a different manner to classical antagonists (e.g., tirofiban), by preventing GPIIb/IIIa activation. Given their mechanism of action, these compounds might avoid the adverse effects of antagonists (paradoxical GPIIb/IIIa activation) and constitute attractive pharmacological tools for the development of tailored agents for the treatment of platelet-dependent thrombosis.

  • 35.
    Esguerra, Mauricio
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Siretskiy, Alexey
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Bello, Xabier
    Hosp Clin Univ Santiago, Fdn Publ Galega Med Xenom, Santiago De Compostela 15706, Spain..
    Sallander, Jessica
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Gutierrez-de-Teran, Hugo
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    GPCR-ModSim: A comprehensive web based solution for modeling G-protein coupled receptors2016In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 44, no W1, p. W455-W462Article in journal (Refereed)
    Abstract [en]

    GPCR-ModSim (http://open.gpcr-modsim.org) is a centralized and easy to use service dedicated to the structural modeling of G-protein Coupled Receptors (GPCRs). 3D molecular models can be generated from amino acid sequence by homology-modeling techniques, considering different receptor conformations. GPCR-ModSim includes a membrane insertion and molecular dynamics (MD) equilibration protocol, which can be used to refine the generated model or any GPCR structure uploaded to the server, including if desired non-protein elements such as orthosteric or allosteric ligands, structural waters or ions. We herein revise the main characteristics of GPCR-ModSim and present new functionalities. The templates used for homology modeling have been updated considering the latest structural data, with separate profile structural alignments built for inactive, partially-active and active groups of templates. We have also added the possibility to perform multiple-template homology modeling in a unique and flexible way. Finally, our new MD protocol considers a series of distance restraints derived from a recently identified conserved network of helical contacts, allowing for a smoother refinement of the generated models which is particularly advised when there is low homology to the available templates. GPCR- ModSim has been tested on the GPCR Dock 2013 competition with satisfactory results.

  • 36.
    Fischer, Nina M.
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Poleto, Marcelo D.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab. Center of Biotechnology, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil .
    Steuer, Jakob
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. Univ Konstanz, Dept Chem, Univ Str 10, D-78457 Constance, Germany.
    van der Spoel, David
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Influence of Na+ and Mg2+ ions on RNA structures studied with molecular dynamics simulations2018In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 46, no 10, p. 4872-4882Article in journal (Refereed)
    Abstract [en]

    The structure of ribonucleic acid (RNA) polymers is strongly dependent on the presence of, in particular Mg2+ cations to stabilize structural features. Only in high-resolution X-ray crystallography structures can ions be identified reliably. Here, we perform molecular dynamics simulations of 24 RNA structures with varying ion concentrations. Twelve of the structures were helical and the others complex folded. The aim of the study is to predict ion positions but also to evaluate the impact of different types of ions (Na+ or Mg2+) and the ionic strength on structural stability and variations of RNA. As a general conclusion Mg2+ is found to conserve the experimental structure better than Na+ and, where experimental ion positions are available, they can be reproduced with reasonable accuracy. If a large surplus of ions is present the added electrostatic screening makes prediction of binding-sites less reproducible. Distinct differences in ion-binding between helical and complex folded structures are found. The strength of binding (Delta G(+) for breaking RNA atom-ion interactions) is found to differ between roughly 10 and 26 kJ/mol for the different RNA atoms. Differences in stability between helical and complex folded structures and of the influence of metal ions on either are discussed.

  • 37.
    Ge, Xueliang
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Biology.
    Mandava, Chandra Sekhar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Biology.
    Lind, Christoffer
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Åqvist, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Sanyal, Suparna
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Biology.
    Complementary charge-based interaction between the ribosomal-stalk protein L7/12 and IF2 is the key to rapid subunit association2018In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 18, p. 4649-4654Article in journal (Refereed)
    Abstract [en]

    The interaction between the ribosomal-stalk protein L7/12 (L12) and initiation factor 2 (IF2) is essential for rapid subunit association, but the underlying mechanism is unknown. Here, we have characterized the L12–IF2 interaction on Escherichia coli ribosomes using site-directed mutagenesis, fast kinetics, and molecular dynamics (MD) simulations. Fifteen individual point mutations were introduced into the C-terminal domain of L12 (L12-CTD) at helices 4 and 5, which constitute the common interaction site for translational GTPases. In parallel, 15 point mutations were also introduced into IF2 between the G4 and G5 motifs, which we hypothesized as the potential L12 interaction sites. The L12 and IF2 mutants were tested in ribosomal subunit association assay in a stopped-flow instrument. Those amino acids that caused defective subunit association upon substitution were identified as the molecular determinants of L12–IF2 interaction. Further, MD simulations of IF2 docked onto the L12-CTD pinpointed the exact interacting partners—all of which were positively charged on L12 and negatively charged on IF2, connected by salt bridges. Lastly, we tested two pairs of charge-reversed mutants of L12 and IF2, which significantly restored the yield and the rate of formation of the 70S initiation complex. We conclude that complementary charge-based interaction between L12-CTD and IF2 is the key for fast subunit association. Considering the homology of the G domain, similar mechanisms may apply for L12 interactions with other translational GTPases.

  • 38.
    Ghahremanpour, Mohammad M.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    van Maaren, Paul J.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ditz, Jonas C.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lindh, Roland
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Theoretical Chemistry.
    van der Spoel, David
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Large-scale calculations of gas phase thermochemistry: Enthalpy of formation, standard entropy, and heat capacity2016In: Journal of Chemical Physics, ISSN 0021-9606, E-ISSN 1089-7690, Vol. 145, no 11, article id 114305Article in journal (Refereed)
    Abstract [en]

    Large scale quantum calculations for molar enthalpy of formation (Delta(f) H-0), standard entropy (S-0), and heat capacity (C-V) are presented. A large data set may help to evaluate quantum thermochemistry tools in order to uncover possible hidden shortcomings and also to find experimental data that might need to be reinvestigated, indeed we list and annotate approximately 200 problematic thermochemistry measurements. Quantum methods systematically underestimate S-0 for flexible molecules in the gas phase if only a single (minimum energy) conformation is taken into account. This problem can be tackled in principle by performing thermochemistry calculations for all stable conformations [Zheng et al., Phys. Chem. Chem. Phys. 13, 10885-10907 (2011)], but this is not practical for large molecules. We observe that the deviation of composite quantum thermochemistry recipes from experimental S-0 corresponds roughly to the Boltzmann equation (S = R ln Omega), where R is the gas constant and Omega the number of possible conformations. This allows an empirical correction of the calculated entropy for molecules with multiple conformations. With the correction we find an RMSD from experiment of approximate to 13 J/mol K for 1273 compounds. This paper also provides predictions of Delta(f) H-0, S-0, and C-V for well over 700 compounds for which no experimental data could be found in the literature. Finally, in order to facilitate the analysis of thermodynamics properties by others we have implemented a new tool obthermo in the OpenBabel program suite [O'Boyle et al., J. Cheminf. 3, 33 (2011)] including a table of reference atomization energy values for popular thermochemistry methods.

  • 39.
    Ghahremanpour, Mohammad M.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    van Maaren, Paul J.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Van Der Spoel, David
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    The Alexandria library, a quantum-chemical database of molecular properties for force field development2018In: Scientific Data, E-ISSN 2052-4463, Vol. 5, article id 180062Article in journal (Refereed)
    Abstract [en]

    Data quality as well as library size are crucial issues for force field development. In order to predict molecular properties in a large chemical space, the foundation to build force fields on needs to encompass a large variety of chemical compounds. The tabulated molecular physicochemical properties also need to be accurate. Due to the limited transparency in data used for development of existing force fields it is hard to establish data quality and reusability is low. This paper presents the Alexandria library as an open and freely accessible database of optimized molecular geometries, frequencies, electrostatic moments up to the hexadecupole, electrostatic potential, polarizabilities, and thermochemistry, obtained from quantum chemistry calculations for 2704 compounds. Values are tabulated and where available compared to experimental data. This library can assist systematic development and training of empirical force fields for a broad range of molecules.

  • 40. Ghisi, Rosella
    et al.
    Vamerali, Teofilo
    Manzetti, Sergio
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
    Accumulation of perfluorinated alkyl substances (PFASs) in agricultural plants: a review.2018In: Environmental ResearchArticle in journal (Refereed)
  • 41.
    Gutiérrez-de-Terán, Hugo