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  • 101.
    Korkmaz, Gürkan
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology.
    Lind, Christoffer
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Åqvist, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Sanyal, Suparna
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology.
    Characterizing an engineered release factor capable of reading all three stop codons2014In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 28, no 1, article id 569.2Article in journal (Other academic)
  • 102.
    Koskiniemi, Sanna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Sun, Song
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Berg, Otto
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Andersson, Dan I.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Selection-driven genome reduction in bacteria2012In: PLOS genetics, ISSN 1553-7404, Vol. 8, no 6, p. e1002787-Article in journal (Refereed)
    Abstract [en]

    Gene loss by deletion is a common evolutionary process in bacteria, as exemplified by bacteria with small genomes that have evolved from bacteria with larger genomes by reductive processes. The driving force(s) for genome reduction remains unclear, and here we examined the hypothesis that gene loss is selected because carriage of superfluous genes confers a fitness cost to the bacterium. In the bacterium Salmonella enterica, we measured deletion rates at 11 chromosomal positions and the fitness effects of several spontaneous deletions. Deletion rates varied over 200-fold between different regions with the replication terminus region showing the highest rates. Approximately 25% of the examined deletions caused an increase in fitness under one or several growth conditions, and after serial passage of wild-type bacteria in rich medium for 1,000 generations we observed fixation of deletions that substantially increased bacterial fitness when reconstructed in a non-evolved bacterium. These results suggest that selection could be a significant driver of gene loss and reductive genome evolution.

  • 103. Kouyoumdjian, Alexandre
    et al.
    Ortie, Erwan
    Tek, Alex
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Pluot, Aurelien
    Henon, Eric
    Chavent, Matthieu
    Baaden, Marc
    Game on, Science - How Video Game Technology may Help Biophysicists Tackle Visualization Challenges2014In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 106, no 2, p. 809A-809AArticle in journal (Other academic)
    Abstract [en]

    The video games industry develops ever more advanced technologies to improve rendering, image quality, ergonomics and user experience of their creations providing very simple to use tools to design new games. In biophysics, only a small number of experts with specialized know-how are able to design interactive visualization applications, typically static computer programs that cannot easily be modified. Are there lessons to be learned from video games? Could their technology help us explore new molecular graphics ideas and render graphics developments accessible to non-specialists?

  • 104. Kruczyk, Marcin
    et al.
    Baltzer, Nicholas
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Mieczkowski, Jakub
    Dramiński, Michał
    Koronacki, Jacek
    Komorowski, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Random Reducts: A Monte Carlo Rough Set-based Method for Feature Selection in Large Datasets2013In: Fundamenta Informaticae, ISSN 0169-2968, E-ISSN 1875-8681, Vol. 127, no 1-4, p. 273-288Article in journal (Refereed)
    Abstract [en]

    An important step prior to constructing a classifier for a very large data set is feature selection. With many problems it is possible to find a subset of attributes that have the same discriminative power as the full data set. There are many feature selection methods but in none of them are Rough Set models tied up with statistical argumentation. Moreover, known methods of feature selection usually discard shadowed features, i.e. those carrying the same or partially the same information as the selected features. In this study we present Random Reducts (RR) - a feature selection method which precedes classification per se. The method is based on the Monte Carlo Feature Selection (MCFS) layout and uses Rough Set Theory in the feature selection process. On synthetic data, we demonstrate that the method is able to select otherwise shadowed features of which the user should be made aware, and to find interactions in the data set.

  • 105.
    Kruczyk, Marcin
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Przanowski, Piotr
    Dabrowski, Michal
    Swiatek-Machado, Karolina
    Mieczkowski, Jakub
    Wallerman, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ronowicz, Anna
    Piotrowski, Arkadiusz
    Wadelius, Claes
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kaminska, Bozena
    Komorowski, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Integration of genome-wide of Stat3 binding and epigenetic modification mapping with transcriptome reveals novel Stat3 target genes in glioma cells2014In: Biochimica et Biophysica Acta, ISSN 0006-3002, E-ISSN 1878-2434, Vol. 1839, no 11, p. 1341-1350Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Signal transducer and activator of transcription 3 (STAT3) is constitutively activated in many human tumors, including gliomas, and regulates the expression of genes implicated in proliferation, survival, apoptosis, angiogenesis and immune regulation. Only a small fraction of those genes has been proven to be direct STAT3 targets. In gliomas, STAT3 can play tumor suppressive or oncogenic roles depending on the tumor genetic background with target genes being largely unknown.

    RESULTS: We used chromatin immunoprecipitation, promoter microarrays and deep sequencing to assess the genome-wide occupancy of phospho (p)-Stat3 and epigenetic modifications of H3K4me3 and H3ac in C6 glioma cells. This combined assessment identified a list of 1200 genes whose promoters have both Stat3 binding sites and epigenetic marks characteristic for actively transcribed genes. The Stat3 and histone markings data were also intersected with a set of microarray data from C6 glioma cells after inhibition of Jak2/Stat3 signaling. Subsequently, we found 284 genes characterized by p-Stat3 occupancy, activating histone marks and transcriptional changes. Novel genes were screened for their potential involvement in oncogenesis, and the most interesting hits were verified by ChIP-PCR and STAT3 knockdown in human glioma cells.

    CONCLUSIONS: Non-random association between silent genes, histone marks and p-Stat3 binding near transcription start sites was observed, consistent with its repressive role in transcriptional regulation of target genes in glioma cells with specific genetic background.

  • 106.
    Kruczyk, Marcin
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Umer, Husen Muhammad
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Enroth, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Komorowski, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Peak Finder Metaserver - a novel application for finding peaks in ChIP-seq data2013In: BMC Bioinformatics, ISSN 1471-2105, E-ISSN 1471-2105, Vol. 14, p. 280-Article in journal (Refereed)
    Abstract [en]

    Background: Finding peaks in ChIP-seq is an important process in biological inference. In some cases, such as positioning nucleosomes with specific histone modifications or finding transcription factor binding specificities, the precision of the detected peak plays a significant role. There are several applications for finding peaks (called peak finders) based on different algorithms (e.g. MACS, Erange and HPeak). Benchmark studies have shown that the existing peak finders identify different peaks for the same dataset and it is not known which one is the most accurate. We present the first meta-server called Peak Finder MetaServer (PFMS) that collects results from several peak finders and produces consensus peaks. Our application accepts three standard ChIP-seq data formats: BED, BAM, and SAM. Results: Sensitivity and specificity of seven widely used peak finders were examined. For the experiments we used three previously studied Transcription Factors (TF) ChIP-seq datasets and identified three of the selected peak finders that returned results with high specificity and very good sensitivity compared to the remaining four. We also ran PFMS using the three selected peak finders on the same TF datasets and achieved higher specificity and sensitivity than the peak finders individually. Conclusions: We show that combining outputs from up to seven peak finders yields better results than individual peak finders. In addition, three of the seven peak finders outperform the remaining four, and running PFMS with these three returns even more accurate results. Another added value of PFMS is a separate report of the peaks returned by each of the included peak finders.

  • 107.
    Kruczyk, Marcin
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Zetterberg, Henrik
    Hansson, Oskar
    Rolstad, Sindre
    Minthon, Lennart
    Wallin, Anders
    Blennow, Kaj
    Komorowski, Jan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Andersson, Mats Gunnar
    Monte Carlo feature selection and rule-based models to predict Alzheimer's disease in mild cognitive impairment2012In: Journal of neural transmission, ISSN 0300-9564, E-ISSN 1435-1463, Vol. 119, no 7, p. 821-831Article in journal (Refereed)
    Abstract [en]

    The objective of the present study was to evaluate a Monte Carlo feature selection (MCFS) and rough set Rosetta pipeline for generating rule-based models as a tool for comprehensive risk estimates for future Alzheimer's disease (AD) in individual patients with mild cognitive impairment (MCI). Risk estimates were generated on the basis of age, gender, Mini-Mental State Examination scores, apolipoprotein E (APOE) genotype and the cerebrospinal fluid (CSF) biomarkers total tau (T-tau), phospho-tau(181) (P-tau) and the 42 amino acid form of amyloid beta (A beta 42) in two sets of longitudinally followed MCI patients (n = 217 in total). The predictive model was created in Rosetta, evaluated with the standard tenfold cross-validation approach and tested on an external set. Features were ranked and selected by the MCFS algorithm. Using the combined pipeline of MCFS and Rosetta, it was possible to predict AD among patients with MCI with an area under the receiver operating characteristics curve of 0.92. Risk estimates were produced for the individual patients and showed good correlation with actual diagnosis in cross validation, and on an external dataset from a new study. Analysis of the importance of attributes showed that the biochemical CSF markers contributed the most to the predictions, and that added value was gained by combining several biochemical markers. Despite a correlation with the biochemical markers, the genetic marker APOE epsilon 4 did not contribute to the predictive power of the model.

  • 108. Kudavalli, Jaya Satyanarayana
    et al.
    Rao, S. Nagaraja
    Bean, David E.
    Sharma, Narain D.
    Boyd, Derek R.
    Fowler, Patrick W.
    Gronert, Scott
    Kamerlin, Shina Caroline Lynn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Keeffe, James R.
    O'Ferrall, Rory A. More
    Base-Catalyzed Dehydration of 3-Substituted Benzene cis-1,2-Dihydrodiols: Stabilization of a Cyclohexadienide Anion Intermediate by Negative Aromatic Hyperconjugation2012In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 134, no 34, p. 14056-14069Article in journal (Refereed)
    Abstract [en]

    Evidence that a 1,2-dihydroxycyclohexadienide anion is stabilized by aromatic "negative hyperconjugation" is described. It complements an earlier inference of "positive" hyperconjugative aromaticity for the cyclohexadienyl cation. The anion is a reactive intermediate in the dehydration of benzene cis-1,2-dihydrodiol to phenol. Rate constants for 3-substituted benzene cis-dihydrodiols are correlated by values with rho = 3.2. Solvent isotope effects for the reactions are k(H2O)/k(D2O) = 1.2-1.8. These measurements are consistent with reaction via a carbanion intermediate or a concerted reaction with a "carbanion-like" transition state. These and other experimental results confirm that the reaction proceeds by a stepwise mechanism, with a change in rate-determining step from proton transfer to the loss of hydroxide ion from the intermediate. Hydrogen isotope exchange accompanying dehydration of the parent benzene cis-1,2-dihydrodiol was not found, and thus, the proton transfer step is subject to internal return. A rate constant of similar to 10(11) s(-1), corresponding to rotational relaxation of the aqueous solvent, is assigned to loss of hydroxide ion from the intermediate. The rate constant for internal return therefore falls in the range 10(11)-10(12) s(-1). From these limiting values and the measured rate constant for hydroxide-catalyzed dehydration, a pK(a) of 30.8 +/- 0.5 was determined for formation of the anion. Although loss of hydroxide ion is hugely exothermic, a concerted reaction is not enforced by the instability of the intermediate. Stabilization by negative hyperconjugation is proposed for 1,2-dihydroxycyclohexadienide and similar anions, and this proposal is supported by additional experimental evidence and by computational results, including evidence for a diatropic ("aromatic") ring current in 3,3-difluorocyclohexadienyl anion.

  • 109. Kuzmenko, Anton
    et al.
    Tankov, Stoyan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    English, Brian P.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Tarassov, Ivan
    Tenson, Tanel
    Kamenski, Piotr
    Elf, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Hauryliuk, Vasili
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Single molecule tracking fluorescence microscopy in mitochondria reveals highly dynamic but confined movement of Tom402011In: Scientific reports, ISSN 2045-2322, Vol. 1, p. 195-Article in journal (Refereed)
    Abstract [en]

    Tom40 is an integral protein of the mitochondrial outer membrane, which as the central component of the Translocase of the Outer Membrane (TOM) complex forms a channel for protein import. We characterize the diffusion properties of individual Tom40 molecules fused to the photoconvertable fluorescent protein Dendra2 with millisecond temporal resolution. By imaging individual Tom40 molecules in intact isolated yeast mitochondria using photoactivated localization microscopy with sub-diffraction limited spatial precision, we demonstrate that Tom40 movement in the outer mitochondrial membrane is highly dynamic but confined in nature, suggesting anchoring of the TOM complex as a whole.

  • 110.
    Lamichhaney, Sangeet
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Fan, Guangyi
    BGI Shenzhen, Shenzhen, Peoples R China.;Univ Macau, Inst Chinese Med Sci, State Key Lab Qual Res Chinese Med, Taipa, Peoples R China..
    Widemo, Fredrik
    Swedish Univ Agr Sci, Dept Wildlife Fish & Environm Studies, S-90183 Umea, Sweden..
    Gunnarsson, Ulrika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Thalmann, Doreen Schwochow
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden.;AgroParisTech, Inst Natl Rech Agron, Genet Anim & Biol Integrat, Jouy En Josas, France..
    Höppner, Marc P.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Kerje, Susanne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Gustafson, Ulla
    Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden..
    Shi, Chengcheng
    BGI Shenzhen, Shenzhen, Peoples R China..
    Zhang, He
    BGI Shenzhen, Shenzhen, Peoples R China..
    Chen, Wenbin
    BGI Shenzhen, Shenzhen, Peoples R China..
    Liang, Xinming
    BGI Shenzhen, Shenzhen, Peoples R China..
    Huang, Leihuan
    BGI Shenzhen, Shenzhen, Peoples R China..
    Wang, Jiahao
    BGI Shenzhen, Shenzhen, Peoples R China..
    Liang, Enjing
    BGI Shenzhen, Shenzhen, Peoples R China..
    Wu, Qiong
    BGI Shenzhen, Shenzhen, Peoples R China..
    Lee, Simon Ming-Yuen
    Univ Macau, Inst Chinese Med Sci, State Key Lab Qual Res Chinese Med, Taipa, Peoples R China..
    Xu, Xun
    BGI Shenzhen, Shenzhen, Peoples R China..
    Höglund, Jacob
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Animal ecology.
    Liu, Xin
    BGI Shenzhen, Shenzhen, Peoples R China..
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Swedish Univ Agr Sci, Dept Anim Breeding & Genet, Uppsala, Sweden.;Texas A&M Univ, Dept Vet Integrat Biosci, College Stn, TX USA..
    Structural genomic changes underlie alternative reproductive strategies in the ruff (Philomachus pugnax)2016In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 48, no 1, p. 84-+Article in journal (Refereed)
    Abstract [en]

    The ruff is a Palearctic wader with a spectacular lekking behavior where highly ornamented males compete for females(1-4). This bird has one of the most remarkable mating systems in the animal kingdom, comprising three different male morphs (independents, satellites and faeders) that differ in behavior, plumage color and body size. Remarkably, the satellite and faeder morphs are controlled by dominant alleles(5,6). Here we have used whole-genome sequencing and resolved the enigma of how such complex phenotypic differences can have a simple genetic basis. The Satellite and Faeder alleles are both associated with a 4.5-Mb inversion that occurred about 3.8 million years ago. We propose an evolutionary scenario where the Satellite chromosome arose by a rare recombination event about 500,000 years ago. The ruff mating system is the result of an evolutionary process in which multiple genetic changes contributing to phenotypic differences between morphs have accumulated within the inverted region.

  • 111.
    Larsson, Daniel
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Exploring the Molecular Dynamics of Proteins and Viruses2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Knowledge about structure and dynamics of the important biological macromolecules — proteins, nucleic acids, lipids and sugars — helps to understand their function. Atomic-resolution structures of macromolecules are routinely captured with X-ray crystallography and other techniques. In this thesis, simulations are used to explore the dynamics of the molecules beyond the static structures.

    Viruses are machines constructed from macromolecules. Crystal structures of them reveal little to no information about their genomes. In simulations of empty capsids, we observed a correlation between the spatial distribution of chloride ions in the solution and the position of RNA in crystals of satellite tobacco necrosis virus (STNV) and satellite tobacco mosaic virus (STMV). In this manner, structural features of the non-symmetric RNA could also be inferred.

    The capsid of STNV binds calcium ions on the icosahedral symmetry axes. The release of these ions controls the activation of the virus particle upon infection. Our simulations reproduced the swelling of the capsid upon removal of the ions and we quantified the water permeability of the capsid. The structure and dynamics of the expanded capsid suggest that the disassembly is initiated at the 3-fold symmetry axis.

    Several experimental methods require biomolecular samples to be injected into vacuum, such as mass-spectrometry and diffractive imaging of single particles. It is therefore important to understand how proteins and molecule-complexes respond to being aerosolized. In simulations we mimicked the dehydration process upon going from solution into the gas phase. We find that two important factors for structural stability of proteins are the temperature and the level of residual hydration. The simulations support experimental claims that membrane proteins can be protected by a lipid micelle and that a non-membrane protein could be stabilized in a reverse micelle in the gas phase. A water-layer around virus particles would impede the signal in diffractive experiments, but our calculations estimate that it should be possible to determine the orientation of the particle in individual images, which is a prerequisite for three-dimensional reconstruction.

    List of papers
    1. Virus Capsid Dissolution Studied by Microsecond Molecular Dynamics Simulations
    Open this publication in new window or tab >>Virus Capsid Dissolution Studied by Microsecond Molecular Dynamics Simulations
    2012 (English)In: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 8, no 5, p. e1002502-Article in journal (Refereed) Published
    Abstract [en]

    Dissolution of many plant viruses is thought to start with swelling of the capsid caused by calcium removal following infection, but no high-resolution structures of swollen capsids exist. Here we have used microsecond all-atom molecular simulations to describe the dynamics of the capsid of satellite tobacco necrosis virus with and without the 92 structural calcium ions. The capsid expanded 2.5% upon removal of the calcium, in good agreement with experimental estimates. The water permeability of the native capsid was similar to that of a phospholipid membrane, but the permeability increased 10-fold after removing the calcium, predominantly between the 2-fold and 3-fold related subunits. The two calcium binding sites close to the icosahedral 3-fold symmetry axis were pivotal in the expansion and capsid-opening process, while the binding site on the 5-fold axis changed little structurally. These findings suggest that the dissociation of the capsid is initiated at the 3-fold axis.

    National Category
    Biophysics Structural Biology
    Identifiers
    urn:nbn:se:uu:diva-171701 (URN)10.1371/journal.pcbi.1002502 (DOI)000305964600012 ()
    Available from: 2012-03-26 Created: 2012-03-26 Last updated: 2017-12-07Bibliographically approved
    2. Screening for the Location of RNA Using the Chloride Ion Distribution in Simulations of Virus Capsids
    Open this publication in new window or tab >>Screening for the Location of RNA Using the Chloride Ion Distribution in Simulations of Virus Capsids
    2012 (English)In: Journal of Chemical Theory and Computation, ISSN 1549-9618, E-ISSN 1549-9626, Vol. 8, no 7, p. 2474-2483Article in journal (Refereed) Published
    Abstract [en]

    The complete structure of the genomic material inside a virus capsid remains elusive, although a limited amount of symmetric nucleic acid can be resolved in the crystal structure of 17 icosahedral viruses. The negatively charged sugar-phosphate backbone of RNA and DNA as well as the large positive charge of the interior surface of the virus capsids suggest that electrostatic complementarity is an important factor in the packaging of the genomes in these viruses. To test how much packing information is encoded by the electrostatic and steric envelope of the capsid interior, we performed extensive all-atom molecular dynamics (MD) simulations of virus capsids with explicit water molecules and solvent ions. The model systems were two small plant viruses in which significant amounts of RNA has been observed by X-ray crystallography: satellite tobacco mosaic virus (STMV, 62% RNA visible) and satellite tobacco necrosis virus (STNV, 34% RNA visible). Simulations of half-capsids of these viruses with no RNA present revealed that the binding sites of RNA correlated well with regions populated by chloride ions, suggesting that it is possible to screen for the binding sites of nucleic acids by determining the equilibrium distribution of negative ions. By including the crystallographically resolved RNA in addition to ions, we predicted the localization of the unresolved RNA in the viruses. Both viruses showed a hot-spot for RNA binding at the S-fold symmetry axis. The MD simulations were compared to predictions of the chloride density based on nonlinear Poisson-Boltzmann equation (PBE) calculations with mobile ions. Although the predictions are superficially similar, the PBE calculations overestimate the ion concentration close to the capsid surface and underestimate it far away, mainly because protein dynamics is not taken into account. Density maps from chloride screening can be used to aid in building atomic models of packaged virus genomes. Knowledge of the principles of genome packaging might be exploited for both antiviral therapy and technological applications.

    National Category
    Structural Biology Biophysics
    Identifiers
    urn:nbn:se:uu:diva-172285 (URN)10.1021/ct3002128 (DOI)000306245900032 ()
    Available from: 2012-04-03 Created: 2012-04-03 Last updated: 2017-12-07Bibliographically approved
    3. Encapsulation of myoglobin in a cetyl trimethylammonium bromide micelle in vacuo: a simulation study
    Open this publication in new window or tab >>Encapsulation of myoglobin in a cetyl trimethylammonium bromide micelle in vacuo: a simulation study
    2009 (English)In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 48, no 5, p. 1006-1015Article in journal (Refereed) Published
    Abstract [en]

    A recently published paper describes encapsulation of myoglobin into cetyl trimethylammonium bromide (CTAB) micelles by electrospray ionization followed by detection using mass spectrometry [Sharon, M., et al. (2007) J. Am. Chem. Soc. 129, 8740-8746]. Here we present molecular dynamics simulations aimed at elucidating the structural transitions that accompany the encapsulation and dehydration processes. Myoglobin associates with CTAB surfactants in solution, but no complete reverse micelle is formed. Upon removal of most of the water and exposure of the system to vacuum, a stable protein-surfactant reverse micelle forms. The surfactants shield the protein to a large extent from dehydration-related conformational changes, in the same manner that a water shell does, as previously described by Patriksson et al. [(2007) Biochemistry 46, 933-945]. Solvated CTAB micelles undergo a rapid inversion when transported to the gas phase and form very stable reverse micelles, independent of the amount of water present.

    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-104076 (URN)10.1021/bi801952f (DOI)000263047900022 ()19154126 (PubMedID)
    Available from: 2009-05-27 Created: 2009-05-27 Last updated: 2017-12-13Bibliographically approved
    4. Structural stability of electrosprayed proteins: temperature and hydration effects
    Open this publication in new window or tab >>Structural stability of electrosprayed proteins: temperature and hydration effects
    Show others...
    2009 (English)In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 11, no 36, p. 8069-8078Article in journal (Refereed) Published
    Abstract [en]

    Electrospray ionization is a gentle method for sample delivery, routinely used in gas-phase studies of proteins. It is crucial for structural investigations that the protein structure is preserved, and a good understanding of how structure is affected by the transition to the gas phase is needed for the tuning of experiments to meet that requirement. Small amounts of residual solvent have been shown to protect the protein, but temperature is important too, although it is not well understood how the latter affects structural details. Using molecular dynamics we have simulated four sparingly hydrated globular proteins (Trp-cage; Ctf, a C-terminal fragment of a bacterial ribosomal protein; ubiquitin; and lysozyme) in vacuum starting at temperatures ranging from 225 K to 425 K. For three of the proteins, our simulations show that a water layer corresponding to 3 angstrom preserves the protein structure in vacuum, up to starting temperatures of 425 K. Only Ctf shows minor secondary structural changes at lower starting temperatures. The structural conservation stems mainly from interactions with the surrounding water. Temperature scales in simulations are not directly translatable into experiments, but the wide temperature range in which we find the proteins to be stable is reassuring for the success of future single particle imaging experiments. The water molecules aggregate in clusters and form patterns on the protein surface, maintaining a reproducible hydrogen bonding network. The simulations were performed mainly using OPLS-AA/L, with cross checks using AMBER03 and GROMOS96 53a6. Only minor differences between the results from the three different force fields were observed.

    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-142196 (URN)10.1039/b903846a (DOI)000269548300033 ()
    External cooperation:
    Available from: 2011-01-13 Created: 2011-01-13 Last updated: 2017-12-11Bibliographically approved
    5. Molecular Dynamics Simulations of a Membrane Protein-Micelle Complex in Vacuo
    Open this publication in new window or tab >>Molecular Dynamics Simulations of a Membrane Protein-Micelle Complex in Vacuo
    2009 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 131, no 46, p. 16606-16607Article in journal (Refereed) Published
    Abstract [en]

    We report the first molecular dynamics simulations of an integral membrane protein in a detergent micelle under vacuum conditions. To mimic the dehydration process in electrospray ionization, the N-terminal outer membrane protein A transmembrane domain (OmpA171) from Escherichia coli embedded in a dodecylphosphocholine (DPC) detergent micelle has been simulated with water shells of varying thickness. Removal of the water molecules leaves the membrane protein relatively unaffected by the vacuum conditions. The major structural change occurs in the surrounding micelle, where the DPC molecules structurally rearrange from a normal-phase micelle with DPC detergents radiating spherically from OmpA171 to a structure where the DPC molecules form a layered onion structure in which the head groups, which strive to interact with each other, form an intermediate layer between the inner layer of tail groups that are expelled to the surface, protruding into the void.

    National Category
    Biological Sciences
    Identifiers
    urn:nbn:se:uu:diva-127396 (URN)10.1021/ja902962y (DOI)000272185400002 ()
    Available from: 2010-07-14 Created: 2010-07-13 Last updated: 2017-12-12Bibliographically approved
    6. Proteins, Lipids, and Water in the Gas Phase
    Open this publication in new window or tab >>Proteins, Lipids, and Water in the Gas Phase
    2011 (English)In: Macromolecular Bioscience, ISSN 1616-5187, E-ISSN 1616-5195, Vol. 11, no 1, p. 50-59Article in journal (Refereed) Published
    Abstract [en]

    Evidence from mass-spectrometry experiments and molecular dynamics simulations suggests that it is possible to transfer proteins, or in general biomolecular aggregates, from solution to the gas-phase without grave impact on the structure. If correct, this allows interpretation of such experiments as a probe of physiological behavior. Here, we survey recent experimental results from mass spectrometry and ion-mobility spectroscopy and combine this with observations based on molecular dynamics simulation, in order to give a comprehensive overview of the state of the art in gas-phase studies. We introduce a new concept in protein structure analysis by determining the fraction of the theoretical possible numbers of hydrogen bonds that are formed in solution and in the gas-phase. In solution on average 43% of the hydrogen bonds is realized, while in vacuo this fraction increases to 56%. The hydrogen bonds stabilizing the secondary structure (alpha-helices, beta-sheets) are maintained to a large degree, with additional hydrogen bonds occurring when side chains make new hydrogen bonds to rest of the protein rather than to solvent. This indicates that proteins that are transported to the gas phase in a native-like manner in many cases will be kinetically trapped in near-physiological structures. Simulation results for lipid-and detergent-aggregates and lipid-coated (membrane) proteins in the gas phase are discussed, which in general point to the conclusion that encapsulating proteins in "something'' aids in the conservation of native-like structure. Isolated solvated micelles of cetyl-tetraammonium bromide quickly turn into reverse micelles whereas dodecyl phosphocholine micelles undergo much slower conversions, and do not quite reach a reverse micelle conformation within 100 ns.

    Keywords
    GROMACS, insulin, lysozyme, myoglobin, OmpA, structures, Trp-Cage, ubiquitin, X-ray
    National Category
    Biological Sciences
    Identifiers
    urn:nbn:se:uu:diva-145221 (URN)10.1002/mabi.201000291 (DOI)000285932600006 ()21136535 (PubMedID)
    External cooperation:
    Available from: 2011-02-08 Created: 2011-02-07 Last updated: 2017-12-11Bibliographically approved
    7. Coherent Diffraction of a Single Virus Particle : The Impact of a Water Layer on the Available Orientational Information
    Open this publication in new window or tab >>Coherent Diffraction of a Single Virus Particle : The Impact of a Water Layer on the Available Orientational Information
    Show others...
    2011 (English)In: Physical Review E. Statistical, Nonlinear, and Soft Matter Physics, ISSN 1539-3755, E-ISSN 1550-2376, Vol. 83, p. 031907-1-031907-5Article in journal (Refereed) Published
    Abstract [en]

    Coherent diffractive imaging using x-ray free-electron lasers (XFELs) may provide a unique opportunity for high-resolution structural analysis of single particles sprayed from an aqueous solution into the laser beam. As a result, diffraction images are measured from randomly oriented objects covered by a water layer. We analyze theoretically how the thickness of the covering water layer influences the structural and orientational information contained in the recorded diffraction images. This study has implications for planned experiments on single-particle imaging with XFELs.

    National Category
    Condensed Matter Physics
    Research subject
    Biology
    Identifiers
    urn:nbn:se:uu:diva-166440 (URN)10.1103/PhysRevE.83.031907 (DOI)000288699900004 ()
    Available from: 2012-01-12 Created: 2012-01-12 Last updated: 2017-12-08Bibliographically approved
  • 112.
    Larsson, Daniel
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Liljas, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology.
    van der Spoel, David
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Virus Capsid Dissolution Studied by Microsecond Molecular Dynamics Simulations2012In: PloS Computational Biology, ISSN 1553-734X, E-ISSN 1553-7358, Vol. 8, no 5, p. e1002502-Article in journal (Refereed)
    Abstract [en]

    Dissolution of many plant viruses is thought to start with swelling of the capsid caused by calcium removal following infection, but no high-resolution structures of swollen capsids exist. Here we have used microsecond all-atom molecular simulations to describe the dynamics of the capsid of satellite tobacco necrosis virus with and without the 92 structural calcium ions. The capsid expanded 2.5% upon removal of the calcium, in good agreement with experimental estimates. The water permeability of the native capsid was similar to that of a phospholipid membrane, but the permeability increased 10-fold after removing the calcium, predominantly between the 2-fold and 3-fold related subunits. The two calcium binding sites close to the icosahedral 3-fold symmetry axis were pivotal in the expansion and capsid-opening process, while the binding site on the 5-fold axis changed little structurally. These findings suggest that the dissociation of the capsid is initiated at the 3-fold axis.

  • 113.
    Larsson, Daniel
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology. 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 and Systems Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Screening for the Location of RNA Using the Chloride Ion Distribution in Simulations of Virus Capsids2012In: Journal of Chemical Theory and Computation, ISSN 1549-9618, E-ISSN 1549-9626, Vol. 8, no 7, p. 2474-2483Article in journal (Refereed)
    Abstract [en]

    The complete structure of the genomic material inside a virus capsid remains elusive, although a limited amount of symmetric nucleic acid can be resolved in the crystal structure of 17 icosahedral viruses. The negatively charged sugar-phosphate backbone of RNA and DNA as well as the large positive charge of the interior surface of the virus capsids suggest that electrostatic complementarity is an important factor in the packaging of the genomes in these viruses. To test how much packing information is encoded by the electrostatic and steric envelope of the capsid interior, we performed extensive all-atom molecular dynamics (MD) simulations of virus capsids with explicit water molecules and solvent ions. The model systems were two small plant viruses in which significant amounts of RNA has been observed by X-ray crystallography: satellite tobacco mosaic virus (STMV, 62% RNA visible) and satellite tobacco necrosis virus (STNV, 34% RNA visible). Simulations of half-capsids of these viruses with no RNA present revealed that the binding sites of RNA correlated well with regions populated by chloride ions, suggesting that it is possible to screen for the binding sites of nucleic acids by determining the equilibrium distribution of negative ions. By including the crystallographically resolved RNA in addition to ions, we predicted the localization of the unresolved RNA in the viruses. Both viruses showed a hot-spot for RNA binding at the S-fold symmetry axis. The MD simulations were compared to predictions of the chloride density based on nonlinear Poisson-Boltzmann equation (PBE) calculations with mobile ions. Although the predictions are superficially similar, the PBE calculations overestimate the ion concentration close to the capsid surface and underestimate it far away, mainly because protein dynamics is not taken into account. Density maps from chloride screening can be used to aid in building atomic models of packaged virus genomes. Knowledge of the principles of genome packaging might be exploited for both antiviral therapy and technological applications.

  • 114. Larsson, Erik
    et al.
    Fredlund Fuchs, Peder
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heldin, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Barkefors, Irmeli
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Bondjers, Cecilia
    Genové, Guillem
    Arrondel, Christelle
    Gerwins, Pär
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Kurschat, Christine
    Schermer, Bernhard
    Benzing, Thomas
    Harvey, Scott J
    Kreuger, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lindahl, Per
    Discovery of microvascular miRNAs using public gene expression data: miR-145 is expressed in pericytes and is a regulator of Fli12009In: Genome Medicine, ISSN 1756-994X, E-ISSN 1756-994X, Vol. 1, no 11, p. 108-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND

    A function for the microRNA (miRNA) pathway in vascular development and angiogenesis has been firmly established. miRNAs with selective expression in the vasculature are attractive as possible targets in miRNA-based therapies. However, little is known about the expression of miRNAs in microvessels in vivo. Here, we identified candidate microvascular-selective miRNAs by screening public miRNA expression datasets.

    METHODS

    Bioinformatics predictions of microvascular-selective expression were validated with real-time quantitative reverse transcription PCR on purified microvascular fragments from mouse. Pericyte expression was shown with in situ hybridization on tissue sections. Target sites were identified with 3' UTR luciferase assays, and migration was tested in a microfluid chemotaxis chamber.

    RESULTS

    miR-145, miR-126, miR-24, and miR-23a were selectively expressed in microvascular fragments isolated from a range of tissues. In situ hybridization and analysis of Pdgfb retention motif mutant mice demonstrated predominant expression of miR-145 in pericytes. We identified the Ets transcription factor Friend leukemia virus integration 1 (Fli1) as a miR-145 target, and showed that elevated levels of miR-145 reduced migration of microvascular cells in response to growth factor gradients in vitro.

    CONCLUSIONS

    miR-126, miR-24 and miR-23a are selectively expressed in microvascular endothelial cells in vivo, whereas miR-145 is expressed in pericytes. miR-145 targets the hematopoietic transcription factor Fli1 and blocks migration in response to growth factor gradients. Our findings have implications for vascular disease and provide necessary information for future drug design against miRNAs with selective expression in the microvasculature.

  • 115.
    Lawson, Michael J.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Petzold, Linda
    Hellander, Andreas
    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, Computational Science.
    Accuracy of the Michaelis–Menten approximation when analysing effects of molecular noise2015In: Journal of the Royal Society Interface, ISSN 1742-5689, E-ISSN 1742-5662, Vol. 12, no 106, p. 20150054:1-10, article id 20150054Article in journal (Refereed)
  • 116. Lemkul, Justin A.
    et al.
    Roux, Benoit
    van der Spoel, David
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    MacKerell, Alexander D., Jr.
    Implementation of Extended Lagrangian Dynamics in GROMACS for Polarizable Simulations Using the Classical Drude Oscillator Model2015In: Journal of Computational Chemistry, ISSN 0192-8651, E-ISSN 1096-987X, Vol. 36, no 19, p. 1473-1479Article in journal (Refereed)
    Abstract [en]

    Explicit treatment of electronic polarization in empirical force fields used for molecular dynamics simulations represents an important advancement in simulation methodology. A straightforward means of treating electronic polarization in these simulations is the inclusion of Drude oscillators, which are auxiliary, charge-carrying particles bonded to the cores of atoms in the system. The additional degrees of freedom make these simulations more computationally expensive relative to simulations using traditional fixed-charge (additive) force fields. Thus, efficient tools are needed for conducting these simulations. Here, we present the implementation of highly scalable algorithms in the GROMACS simulation package that allow for the simulation of polarizable systems using extended Lagrangian dynamics with a dual Nose-Hoover thermostat as well as simulations using a full self-consistent field treatment of polarization. The performance of systems of varying size is evaluated, showing that the present code parallelizes efficiently and is the fastest implementation of the extended Lagrangian methods currently available for simulations using the Drude polarizable force field.

  • 117.
    Liljas, Anders
    et al.
    Department of Biochemistry and Structural Biology, Lund University.
    Ehrenberg, Måns
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology.
    Åqvist, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Comment on "The mechanism for activation of GTP hydrolysis on the ribosome"2011In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 333, no 6038, p. 37-Article in journal (Refereed)
    Abstract [en]

    Voorhees et al. (Reports, 5 November 2010, p. 835) determined the structure of elongation factor Tu (EF-Tu) and aminoacyl–transfer RNA bound to the ribosome with a guanosine triphosphate (GTP) analog. However, their identification of histidine-84 of EF-Tu as deprotonating the catalytic water molecule is problematic in relation to their atomic structure; the terminal phosphate of GTP is more likely to be the proper proton acceptor.

  • 118.
    Lind, Christoffer
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Sund, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Åqvist, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Codon-reading specificities of mitochondrial release factors and translation termination at non-standard stop codons2013In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 4Article in journal (Refereed)
    Abstract [en]

    A key feature of mitochondrial translation is the reduced number of transfer RNAs and reassignment of codons. For human mitochondria, a major unresolved problem is how the set of stop codons are decoded by the release factors mtRF1a and mtRF1. Here we present three-dimensional structural models of human mtRF1a and mtRF1 based on their homology to bacterial RF1 in the codon recognition domain, and the strong conservation between mitochondrial and bacterial ribosomal RNA in the decoding region. Sequence changes in the less homologous mtRF1 appear to be correlated with specific features of the mitochondrial rRNA. Extensive computer simulations of the complexes with the ribosomal decoding site show that both mitochondrial factors have similar specificities and that neither reads the putative vertebrate stop codons AGA and AGG. Instead, we present a structural model for a mechanism by which the ICT1 protein causes termination by sensing the presence of these codons in the A-site of stalled ribosomes.

  • 119.
    Lindén, Martin
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Elf, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Single Molecule Tracking in Living Cells: Multistep Reactions, Simulated Microscopy and New Analysis Methods2015In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 108, no 2, p. 360A-360AArticle in journal (Other academic)
  • 120. Lourenco, Tuanan C.
    et al.
    Coelho, Mariny F. C.
    Ramalho, Teodorico C.
    van der Spoel, David
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Costa, Luciano T.
    Insights on the Solubility of CO2 in 1-Ethyl-3-methylimidazolium Bis(trifluoromethylsulfonyl)imide from the Microscopic Point of View2013In: Environmental Science and Technology, ISSN 0013-936X, E-ISSN 1520-5851, Vol. 47, no 13, p. 7421-7429Article in journal (Refereed)
    Abstract [en]

    Emissions of greenhouse gases due to human activities have been well documented as well as the effects on global warming resulting from it. Efforts to reduce greenhouse gases at the source are crucial to curb climate change, but due to insignificant economic incentives to reduce usage of fossil fuels, not a lot of progress has been made by this route. This necessitates additional measures to reduce the occurrence of greenhouse gases in the atmosphere. Here we used theoretical methods to study the solubility of carbon dioxide in ionic liquids (ILs) since sequestration of CO2 in ILs has been proposed as a possible technology for reducing the emissions of CO2 to the atmosphere. Ionic liquids form a class of solvents with melting temperatures below 100 degrees C and, due to very low vapor pressures, which are not volatile. We have performed molecular dynamics (MD) simulations of 1-ethyl-3-methylimidazolium (C(2)mim) bis(trifluoromethylsulfonyl)imide (Tf2N) and its mixtures with carbon dioxide in order to investigate the CO2 concentration effect on the CO2-cation and CO2-anion interactions. A systematic investigation of CO2 concentration effects on resulting equilibrium liquid structure, and the local environment of the ions is provided The Quantum Theory of Atoms in Molecules (QTAIM) was used to determine the interaction energy for CO2-cation and CO2-anion complexes from uncorrelated structures derived from MD simulations. A spatial distribution function analysis demonstrates the specific interactions between CO2 and the ionic liquid. Our findings indicate that the total volume of the system increases with the CO2 concentration, with a molar volume of CO2 of about 0.038 L/mol, corresponding to liquid CO2 under a pressure of 100 bar. In other words, the IL effectively pressurizes the CO2 inside its matrix. The thermodynamics of CO2 solvation in C2 min-Tf2N were computed using free energy techniques, and the solubility of CO2 is found to be higher in this IL (-3.7 +/- 1 kcal/mol) than in water (+0.2 kJ/mol), predominantly due to anion-CO2 interactions.

  • 121. Lundborg, Magnus
    et al.
    Apostolov, Rossen
    Spångberg, Daniel
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Structural Chemistry.
    Gardenäs, Anders
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    van der Spoel, David
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Lindahl, Erik
    An Efficient and Extensible Format, Library, and API for Binary Trajectory Data from Molecular Simulations2014In: Journal of Computational Chemistry, ISSN 0192-8651, E-ISSN 1096-987X, Vol. 35, no 3, p. 260-269Article in journal (Refereed)
    Abstract [en]

    Molecular dynamics simulations is an important application in theoretical chemistry, and with the large high-performance computing resources available today the programs also generate huge amounts of output data. In particular in life sciences, with complex biomolecules such as proteins, simulation projects regularly deal with several terabytes of data. Apart from the need for more cost-efficient storage, it is increasingly important to be able to archive data, secure the integrity against disk or file transfer errors, to provide rapid access, and facilitate exchange of data through open interfaces. There is already a whole range of different formats used, but few if any of them (including our previous ones) fulfill all these goals. To address these shortcomings, we present Trajectory Next Generation (TNG)a flexible but highly optimized and efficient file format designed with interoperability in mind. TNG both provides state-of-the-art multiframe compression as well as a container framework that will make it possible to extend it with new compression algorithms without modifications in programs using it. TNG will be the new file format in the next major release of the GROMACS package, but it has been implemented as a separate library and API with liberal licensing to enable wide adoption both in academic and commercial codes. 

  • 122.
    Luo, Jinghui
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. Biophysical Structural Chemistry, University of Leiden.
    van Loo, Bert
    University of Cambridge, Department of Biochemistry.
    Kamerlin, Lynn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Examining the promiscuous phosphatase activity of Pseudomonas aeruginosa arylsulfatase: A comparison to analogous phosphatases2012In: Proteins: Structure, Function and Bioinformatics, ISSN 1097-0134, Vol. 80, no 4, p. 1211-1226Article in journal (Refereed)
    Abstract [en]

    Pseudomonas aeruginosa arylsulfatase (PAS) is a bacterial sulfatase capable ofhydrolyzing a range of sulfate esters. Recently, it has been demonstrated to also show very high proficiency for phosphate ester hydrolysis. Such proficient catalytic promiscuity is significant, as promiscuity has been suggested to play an important role in enzyme evolution. Additionally, a comparative study of the hydrolyses of the p-nitrophenyl phosphate and sulfate monoesters in aqueous solution has demonstrated that despite superficial similarities, the two reactions proceed through markedly different transition states with very different solvation effects, indicating that the requirements for the efficient catalysis of the two reactions by an enzyme will also be very different (and yet they are both catalyzed by thesame active site). This work explores the promiscuous phosphomonoesterase activity ofPAS. Specifically, we have investigated the identity of the most likely base for the initial activation of the unusual formylglycine hydrate nucleophile (which is common to many sulfatases), and demonstrate that a concerted substrate-as-base mechanism is fully consistent with the experimentally observed data. This is very similar to other related systems, and suggests that, as far as the phosphomonoesterase activity of PAS is concerned, the sulfatase behaves like a classical phosphatase, despite the fact that such a mechanism is unlikely to be available to the native substrate (based on pKa considerations and studies of model systems). Understanding such catalytic versatility can be used to design novel artificial enzymes that are far more proficient than the current generation ofdesigner enzymes. 

  • 123.
    Luo, Jinghui
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    van Loo, Bert
    Kamerlin, Shina C. L.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Catalytic promiscuity in Pseudomonas aeruginosa arylsulfatase as an example of chemistry-driven protein evolution2012In: FEBS Letters, ISSN 0014-5793, E-ISSN 1873-3468, Vol. 586, no 11, p. 1622-1630Article in journal (Refereed)
    Abstract [en]

    In recent years, it has become increasingly clear that many enzymes are catalytically "promiscuous". This can provide a springboard for protein evolution, allowing enzymes to acquire novel functionality without compromising their native activities. We present here a detailed study of Pseudomonas aeruginosa arylsulfatase (PAS), which catalyzes the hydrolysis of a number of chemically distinct substrates, with proficiencies comparable to that towards its native reaction. We demonstrate that the main driving force for the promiscuity is the ability to exploit the electrostatic preorganization of the active site for the native substrate, providing an example of chemistry-driven protein evolution.

  • 124. Luo, Jinghui
    et al.
    Yu, Chien-Hung
    Yu, Huixin
    Borstnar, Rok
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Kamerlin, Lynn
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Graslund, Astrid
    Abrahams, Jan Pieter
    Warmlander, Sebastian K. T. S.
    Cellular Polyamines Promote Amyloid-Beta (A beta) Peptide Fibrillation and Modulate the Aggregation Pathways2013In: ACS Chemical Neuroscience, ISSN 1948-7193, E-ISSN 1948-7193, Vol. 4, no 3, p. 454-462Article in journal (Refereed)
    Abstract [en]

    The cellular polyamines spermine, spermidine, and their metabolic precursor putrescine, have long been associated with cell-growth, tumor-related gene regulations, and Alzheimer's disease. Here, we show by in vitro spectroscopy and AFM imaging, that these molecules promote aggregation of amyloid-beta (A beta) peptides into fibrils and modulate the aggregation pathways. NMR measurements showed that the three polyamines share a similar binding mode to monomeric A beta(1-40) peptide. Kinetic ThT studies showed that already very low polyamine concentrations promote amyloid formation: addition of 10 mu M spermine (normal intracellular concentration is similar to 1 mM) significantly decreased the lag and transition times of the aggregation process. Spermidine and putrescine additions yielded similar but weaker effects. CD measurements demonstrated that the three polyamines induce different aggregation pathways, involving different forms of induced secondary structure. This is supported by AFM images showing that the three polyamines induce A beta(1-40) aggregates with different morphologies. The results reinforce the notion that designing suitable ligands which modulate the aggregation of A beta peptides toward minimally toxic pathways may be a possible therapeutic strategy for Alzheimer's disease.

  • 125.
    Mahmutovic, Anel
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Reaction-Diffusion kinetics of Protein DNA Interactions2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Transcription factors need to rapidly find one specific binding site among millions of nonspecific sites on the chromosomal DNA. In this thesis I use various aspects of reaction-diffusion theory to investigate the interaction between proteins and DNA and to explain the searching, finding and binding to specific operator sites. Using molecular dynamics methods we calculate the free energy profile for the model protein LacI as it leaves a nonspecific stretch of DNA and as it slides along DNA. Based on the free energy profiles we estimate the microscopic dissociation rate constant, kdmicro ~1.45×104s-1, and the 1D diffusion coefficient, D1 ~ 0.05-0.29 μm2s-1 (2-40μs to slide 1 basepair (bp)). At a non-atomistic level of detail we estimate the number of microscopic rebindings before a macroscopic dissociation occurs which leads to the  macroscopic residence time, τDmacro ~ 48±12ms resulting in a in vitro sliding length estimate of 135-345bp.

    When we fit the DNA interaction parameters for in vivo conditions to recent single molecule in vivo experiments we conclude that neither hopping nor intersegment transfer contribute to the target search for the LacI dimer, that it appears to bind the specific Osym operator site as soon as it slides into it, and that the sliding length is around 40bp in the cell. The estimated in vivo D1 ~ 0.025 μm2s-1 is higher than expected from estimates of D1 based on viscosity and the atomistic simulations. Surprisingly, we were also forced to conclude that the nonspecific association for the LacI dimer appeared reaction limited which is in conflict with the free energy profile. This inconsistency is resolved by allowing for steric effects. Using reaction-diffusion theory and simulations we show that an apparent reaction limited association can be diffusion limited if geometry and steric effects are taken into account. Furthermore, the simulations show that a protein binds ~2 times faster to a DNA molecule with a helical reactive patch than to a stripe patch running along the length of the DNA. This facilitated binding has a direct impact on the search time especially in the presence of other DNA binding proteins.

    List of papers
    1. What matters for lac repressor search in vivo-sliding, hopping, intersegment transfer, crowding on DNA or recognition?
    Open this publication in new window or tab >>What matters for lac repressor search in vivo-sliding, hopping, intersegment transfer, crowding on DNA or recognition?
    2015 (English)In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 43, no 7, p. 3454-3464Article in journal (Refereed) Published
    Abstract [en]

    We have investigated which aspects of transcription factor DNA interactions are most important to account for the recent in vivo search time measurements for the dimeric lac repressor. We find the best agreement for a sliding model where non-specific binding to DNA is improbable at first contact and the sliding LacI protein binds at high probability when reaching the specific O-sym operator. We also find that the contribution of hopping to the overall search speed is negligible although physically unavoidable. The parameters that give the best fit reveal sliding distances, including hopping, close to what has been proposed in the past, i.e. similar to 40 bp, but with an unexpectedly high 1D diffusion constant on non-specific DNA sequences. Including a mechanism of inter-segment transfer between distant DNA segments does not bring down the 1D diffusion to the expected fraction of the in vitro value. This suggests a mechanism where transcription factors can slide less hindered in vivo than what is given by a simple viscosity scaling argument or that a modification of the model is needed. For example, the estimated diffusion rate constant would be consistent with the expectation if parts of the chromosome, away from the operator site, were inaccessible for searching.

    National Category
    Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-256544 (URN)10.1093/nar/gkv207 (DOI)000354722500012 ()25779051 (PubMedID)
    Available from: 2015-06-25 Created: 2015-06-24 Last updated: 2017-12-04Bibliographically approved
    2. Lost in presumption: stochastic reactions in spatial models
    Open this publication in new window or tab >>Lost in presumption: stochastic reactions in spatial models
    2012 (English)In: Nature Methods, ISSN 1548-7091, E-ISSN 1548-7105, Vol. 9, no 12, p. 1163-1166Article in journal (Refereed) Published
    Abstract [en]

    Physical modeling is increasingly important for generating insights into intracellular processes. We describe situations in which combined spatial and stochastic aspects of chemical reactions are needed to capture the relevant dynamics of biochemical systems.

    National Category
    Biochemistry and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-191793 (URN)10.1038/nmeth.2253 (DOI)000312093500016 ()
    Available from: 2013-01-14 Created: 2013-01-14 Last updated: 2017-12-06
    3. Transcription-factor binding and sliding on DNA studied using micro- and macroscopic models
    Open this publication in new window or tab >>Transcription-factor binding and sliding on DNA studied using micro- and macroscopic models
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    2013 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 110, no 49, p. 19796-19801Article in journal (Refereed) Published
    Abstract [en]

    Transcription factors search for specific operator sequences by alternating rounds of 3D diffusion with rounds of 1D diffusion (sliding) along the DNA. The details of such sliding have largely been beyond direct experimental observation. For this purpose we devised an analytical formulation of umbrella sampling along a helical coordinate, and from extensive and fully atomistic simulations we quantified the free-energy landscapes that underlie the sliding dynamics and dissociation kinetics for the LacI dimer. The resulting potential of mean force distributions show a fine structure with an amplitude of 1 k(B)T for sliding and 12 kBT for dissociation. Based on the free-energy calculations the repressor slides in close contact with DNA for 8 bp on average before making a microscopic dissociation. By combining the microscopic molecular-dynamics calculations with Brownian simulation including rotational diffusion from the microscopically dissociated state we estimate a macroscopic residence time of 48 ms at the same DNA segment and an in vitro sliding distance of 240 bp. The sliding distance is in agreement with previous in vitro sliding-length estimates. The in vitro prediction for the macroscopic residence time also compares favorably to what we measure by single-molecule imaging of nonspecifically bound fluorescently labeled LacI in living cells. The investigation adds to our understanding of transcription-factor search kinetics and connects the macro-/mesoscopic rate constants to the microscopic dynamics.

    Keywords
    facilitated diffusion, lac operon, lac repressors, gene regulation
    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-213898 (URN)10.1073/pnas.1307905110 (DOI)000327744900041 ()
    External cooperation:
    Available from: 2014-01-06 Created: 2014-01-05 Last updated: 2017-12-06Bibliographically approved
    4. MesoRD 1.0: Stochastic reaction-diffusion simulations in the microscopic limit
    Open this publication in new window or tab >>MesoRD 1.0: Stochastic reaction-diffusion simulations in the microscopic limit
    2012 (English)In: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 28, no 23, p. 3155-3157Article in journal (Refereed) Published
    Abstract [en]

    MesoRD is a tool for simulating stochastic reaction-diffusion systems as modeled by the reaction diffusion master equation. The simulated systems are defined in the Systems Biology Markup Language with additions to define compartment geometries. MesoRD 1.0 supports scale-dependent reaction rate constants and reactions between reactants in neighbouring subvolumes. These new features make it possible to construct physically consistent models of diffusion-controlled reactions also at fine spatial discretization.

    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-192453 (URN)10.1093/bioinformatics/bts584 (DOI)000311902700025 ()
    Available from: 2013-01-23 Created: 2013-01-21 Last updated: 2017-12-06Bibliographically approved
    5. The lac repressor displays facilitated diffusion in living cells
    Open this publication in new window or tab >>The lac repressor displays facilitated diffusion in living cells
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    2012 (English)In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 336, no 6088, p. 1595-1598Article in journal (Refereed) Published
    Abstract [en]

    Transcription factors (TFs) are proteins that regulate the expression of genes by binding sequence-specific sites on the chromosome. It has been proposed that to find these sites fast and accurately, TFs combine one-dimensional (1D) sliding on DNA with 3D diffusion in the cytoplasm. This facilitated diffusion mechanism has been demonstrated in vitro, but it has not been shown experimentally to be exploited in living cells. We have developed a single-molecule assay that allows us to investigate the sliding process in living bacteria. Here we show that the lac repressor slides 45 ± 10 base pairs on chromosomal DNA and that sliding can be obstructed by other DNA-bound proteins near the operator. Furthermore, the repressor frequently (>90%) slides over its natural lacO(1) operator several times before binding. This suggests a trade-off between rapid search on nonspecific sequences and fast binding at the specific sequence.

    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-176861 (URN)10.1126/science.1221648 (DOI)000305507500062 ()22723426 (PubMedID)
    External cooperation:
    Available from: 2012-06-26 Created: 2012-06-26 Last updated: 2017-12-07Bibliographically approved
    6. The helical structure of DNA facilitates binding
    Open this publication in new window or tab >>The helical structure of DNA facilitates binding
    2016 (English)In: Journal of Physics A: Mathematical and Theoretical, ISSN 1751-8113, E-ISSN 1751-8121, Vol. 9, no 36, article id 364002Article in journal (Other academic) Published
    Abstract [en]

    The helical structure of DNA imposes constraints on the rate of diffusion-limited protein binding. Here we solve the reaction-diffusion equations for DNA-like geometries and extend with simulations when necessary. We find that the helical structure can make binding to the DNA more than twice as fast compared to a case where DNA would be reactive only along one side. We also find that this rate advantage remains when the contributions from steric constraints and rotational diffusion of the DNA-binding protein are included. Furthermore, we find that the association rate is insensitive to changes in the steric constraints on the DNA in the helix geometry, while it is much more dependent on the steric constraints on the DNA-binding protein. We conclude that the helical structure of DNA facilitates the nonspecific binding of transcription factors and structural DNA-binding proteins in general.

    Keywords
    reaction-diffusion equation; steric constraints; helix geometry; diffusion limited
    National Category
    Biophysics
    Identifiers
    urn:nbn:se:uu:diva-263526 (URN)10.1088/1751-8113/49/36/364002 (DOI)000383512000002 ()
    Funder
    EU, European Research CouncilKnut and Alice Wallenberg Foundation
    Available from: 2015-10-02 Created: 2015-10-02 Last updated: 2017-12-01Bibliographically approved
  • 126.
    Mahmutovic, Anel
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Berg, Otto G.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Elf, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    What matters for lac repressor search in vivo-sliding, hopping, intersegment transfer, crowding on DNA or recognition?2015In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 43, no 7, p. 3454-3464Article in journal (Refereed)
    Abstract [en]

    We have investigated which aspects of transcription factor DNA interactions are most important to account for the recent in vivo search time measurements for the dimeric lac repressor. We find the best agreement for a sliding model where non-specific binding to DNA is improbable at first contact and the sliding LacI protein binds at high probability when reaching the specific O-sym operator. We also find that the contribution of hopping to the overall search speed is negligible although physically unavoidable. The parameters that give the best fit reveal sliding distances, including hopping, close to what has been proposed in the past, i.e. similar to 40 bp, but with an unexpectedly high 1D diffusion constant on non-specific DNA sequences. Including a mechanism of inter-segment transfer between distant DNA segments does not bring down the 1D diffusion to the expected fraction of the in vitro value. This suggests a mechanism where transcription factors can slide less hindered in vivo than what is given by a simple viscosity scaling argument or that a modification of the model is needed. For example, the estimated diffusion rate constant would be consistent with the expectation if parts of the chromosome, away from the operator site, were inaccessible for searching.

  • 127.
    Mahmutovic, Anel