uu.seUppsala University Publications
Change search
Refine search result
2345 201 - 236 of 236
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Rows per page
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sort
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
Select
The maximal number of hits you can export is 250. When you want to export more records please use the Create feeds function.
  • 201. Tirel, Emmanuel Y.
    et al.
    Bellamy, Zoe
    Adams, Harry
    Lebrun, Vincent
    Duarte, Fernanda
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Williams, Nicholas H.
    Catalytic Zinc Complexes for Phosphate Diester Hydrolysis2014In: Angewandte Chemie International Edition, ISSN 1433-7851, E-ISSN 1521-3773, Vol. 53, no 31, p. 8246-8250Article in journal (Refereed)
    Abstract [en]

    Creating efficient artificial catalysts that can compete with biocatalysis has been an enduring challenge which has yet to be met. Reported herein is the synthesis and characterization of a series of zinc complexes designed to catalyze the hydrolysis of phosphate diesters. By introducing a hydrated aldehyde into the ligand we achieve turnover for DNA-like substrates which, combined with ligand methylation, increases reactivity by two orders of magnitude. In contrast to current orthodoxy and mechanistic explanations, we propose a mechanism where the nucleophile is not coordinated to the metal ion, but involves a tautomer with a more effective Lewis acid and more reactive nucleophile. This data suggests a new strategy for creating more efficient metal ion based catalysts, and highlights a possible mode of action for metalloenzymes.

  • 202.
    Tugues, Sonia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Honjo, Satoshi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    König, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Padhan, Narendra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Kroon, Jeffrey
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Gualandi, Laura
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Li, Xiujuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Barkefors, Irmeli
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Thijssen, Victor L.
    Griffioen, Arjan W.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Tetraspanin CD63 Promotes Vascular Endothelial Growth Factor Receptor 2-beta 1 Integrin Complex Formation, Thereby Regulating Activation and Downstream Signaling in Endothelial Cells in Vitro and in Vivo2013In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 288, no 26, p. 19060-19071Article in journal (Refereed)
    Abstract [en]

    CD63 is a member of the transmembrane-4 glycoprotein superfamily (tetraspanins) implicated in the regulation of membrane protein trafficking, leukocyte recruitment, and adhesion processes. We have investigated the involvement of CD63 in endothelial cell (EC) signaling downstream of beta 1 integrin and VEGF. We report that silencing of CD63 in primary ECs arrested capillary sprouting and tube formation in vitro because of impaired adhesion and migration of ECs. Mechanistically, CD63 associated with both beta 1 integrin and the main VEGF receptor on ECs, VEGFR2. Our data suggest that CD63 serves to bridge between beta 1 integrin and VEGFR2 because CD63 silencing disrupted VEGFR2-beta 1 integrin complex formation identified using proximity ligation assays. Signaling downstream of beta 1 integrin and VEGFR2 was attenuated in CD63-silenced cells, although their cell surface expression levels remained unaffected. CD63 was furthermore required for efficient internalization of VEGFR2 in response to VEGF. Importantly, systemic delivery of VEGF failed to potently induce VEGFR2 phosphorylation and downstream signaling in CD63-deficient mouse lungs. Taken together, our findings demonstrate a previously unrecognized role for CD63 in coordinated integrin and receptor tyrosine kinase signaling in vitro and in vivo.

  • 203.
    Ullman, Gustaf
    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. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computational Science.
    Walldén, Mats
    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.
    Marklund, Erik 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.
    Mahmutovic, Anel
    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.
    Razinkov, Ivan
    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.
    High-throughput gene expression analysis at the level of single proteins using a microfluidic turbidostat and automated cell tracking2013In: Philosophical Transactions of the Royal Society of London. Biological Sciences, ISSN 0962-8436, E-ISSN 1471-2970, Vol. 368, no 1611, p. 20120025:1-8Article in journal (Refereed)
  • 204.
    Umer, Husen M.
    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.
    Khaliq, Zeeshan
    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.
    Marzouka, Nour-al-dain
    Department of Clinical Sciences, Faculty of Medicine, Lund University.
    Smolinska, Karolina
    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.
    Wadelius, Claes
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    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 and Systems Biology. nstitute of Computer Science, Polish Academy of Sciences, Warsaw, Poland.
    funMotifs: Tissue-specific transcription factor motifsManuscript (preprint) (Other academic)
  • 205.
    van der Spoel, David
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Hess, Berk
    GROMACS: the road ahead2011In: Wiley Interdisciplinary Reviews: Computational Molecular Science, ISSN 1759-0876, Vol. 1, no 5, p. 710-715Article in journal (Refereed)
    Abstract [en]

    Molecular dynamics (MD) simulations form a powerful tool that is complementary to experiments and theory. They allow detailed investigations of both biological and chemical systems at the atomic level at timescales ranging from femtoseconds to milliseconds. Mechanisms and processes not accessible to experimental techniques can be followed in 'real time', and hypotheses based on experiments or theoretical arguments can be tested. Limits on the accuracy of results are mainly due to the physical models, the ratio of the complexity of the problem and the amount of computer time. Here, we review the state of the art in MD simulations with a focus on imminent challenges for the GROMACS (GROningen MAchine for Chemical Simulation) software. New hardware puts new requirements on software, while the breadth of applications and the amount of physical models implemented are increasing rapidly, highlighting shortcomings in the architecture of the programs. We sketch a road map for a popular scientific software package and discuss some of the choices to be made.

  • 206.
    van der Spoel, David
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Marklund, Erik G.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Larsson, Daniel S. D.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Caleman, Carl
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Proteins, Lipids, and Water in the Gas Phase2011In: Macromolecular Bioscience, ISSN 1616-5187, E-ISSN 1616-5195, Vol. 11, no 1, p. 50-59Article in journal (Refereed)
    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.

  • 207.
    van der Spoel, David
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Seibert, M Marvin
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular biophysics.
    Protein folding kinetics and thermodynamics from atomistic simulations2006In: Physical Review Letters, ISSN 0031-9007, E-ISSN 1079-7114, Vol. 96, no 23, p. 238102-Article in journal (Refereed)
    Abstract [en]

    Determining protein folding kinetics and thermodynamics from all-atom molecular dynamics (MD) simulations without using experimental data represents a formidable scientific challenge because simulations can easily get trapped in local minima on rough free energy landscapes. This necessitates the computation of multiple simulation trajectories, which can be independent from each other or coupled in some manner, as, for example, in the replica exchange MD method. Here we present results obtained with a new analysis tool that allows the deduction of faithful kinetics data from a heterogeneous ensemble of simulation trajectories. The method is demonstrated on the decapeptide Chignolin for which we predict folding and unfolding time constants of 1.0±0.3 and 2.6±0.4  μs, respectively. We also derive the energetics of folding, and calculate a realistic melting curve for Chignolin.

  • 208.
    van der Spoel, David
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    van Maaren, Paul J.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Caleman, Carl
    Coherent Imaging Division, Center for Free-Electron Laser Science, Deutsches Elektronen-Synchrotron Notkestrasse 85, DE-22607 Hamburg, Germany .
    GROMACS molecule & liquid database2012In: Bioinformatics, ISSN 1367-4803, E-ISSN 1367-4811, Vol. 28, no 5, p. 752-753Article in journal (Refereed)
    Abstract [en]

    Motivation:

    The molecular dynamics simulation package GROMACS is a widely used tool used in a broad range of different applications within physics, chemistry and biology. It is freely available, user friendly and extremely efficient. The GROMACS software is force field agnostic, and compatible with many molecular dynamics force fields; coarse- grained, unified atom, all atom as well as polarizable models based on the charge on a spring concept. To validate simulations, it is necessary to compare results from the simulations to experimental data. To ease the process of setting up topologies and structures for simulations, as well as providing pre- calculated physical properties along with experimental values for the same we provide a web- based database, containing 145 organic molecules at present.

    Results

    Liquid properties of 145 organic molecules have been simulated using two different force fields, OPLS all atom and Generalized Amber Force Field. So far, eight properties have been calculated (the density, enthalpy of vaporization, surface tension, heat capacity at constant volume and pressure, isothermal compressibility, volumetric expansion coefficient and the static dielectric constant). The results, together with experimental values are available through the database, along with liquid structures and topologies for the 145 molecules, in the two force fields.

  • 209. van Lun, Michiel
    et al.
    Hub, Jochen S.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    van der Spoel, David
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Andersson, Inger
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular biophysics.
    CO2 and O-2 Distribution in Rubisco Suggests the Small Subunit Functions as a CO2 Reservoir2014In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 136, no 8, p. 3165-3171Article in journal (Refereed)
    Abstract [en]

    Protein gas interactions are important in biology. The enzyme ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) catalyzes two competing reactions involving CO2 and O-2 as substrates. Carboxylation of the common substrate ribulose-1,5-bisphosphate leads to photosynthetic carbon assimilation, while the oxygenation reaction competes with carboxylation and reduces photosynthetic productivity. The migration of the two gases in and around Rubisco was investigated using molecular dynamics simulations. The results indicate that at equal concentrations of the gases, Rubisco binds CO2 stronger than it does O-2. Amino acids with small hydrophobic side chains are the most proficient in attracting CO2, indicating a significant contribution of the hydrophobic effect in the interaction. On average, residues in the small subunit bind approximately twice as much CO2 as do residues in the large subunit. We did not detect any cavities that would provide a route to the active site for the gases. Instead, CO2 appears to be guided toward the active site through a CO2 binding region around the active site opening that extends to the closest neighboring small subunits. Taken together, these results suggest the small subunit may function as a "reservoir" for CO2 storage.

  • 210. van Lun, Michiel
    et al.
    van der Spoel, David
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Andersson, Inger
    Sveriges lantbruksuniversitet.
    Subunit Interface Dynamics in Hexadecameric Rubisco2011In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 411, no 5, p. 1083-1098Article in journal (Refereed)
    Abstract [en]

    Ribulose-1,5-bisphosphate (RuBP) carboxylase/oxygenase (Rubisco) plays an important role in the global carbon cycle as a hub for biomass. Rubisco catalyzes not only the carboxylation of RuBP with carbon dioxide but also a competing oxygenation reaction of RuBP with a negative impact on photosynthetic yield. The functional active site is built from two large (L) subunits that form a dimer. The octameric core of four L(2) dimers is held at each end by a cluster of four small (S) subunits, forming a hexadecamer. Each large subunit contacts more than one S subunit. These interactions exploit the dynamic flexibility of Rubisco, which we address in this study. Here, we describe seven different types of interfaces of hexadecameric Rubisco. We have analyzed these interfaces with respect to the size of the interface area and the number of polar interactions, including salt bridges and hydrogen bonds in a variety of Rubisco enzymes from different organisms and different kingdoms of life, including the Rubisco-like proteins. We have also performed molecular dynamics simulations of Rubisco from Chlamydomonas reinhardtii and mutants thereof. From our computational analyses, we propose structural checkpoints of the S subunit to ensure the functionality and/or assembly of the Rubisco holoenzyme. These checkpoints appear to fine-tune the dynamics of the enzyme in a way that could influence enzyme performance.

  • 211.
    Wagner, Gerhart E. H.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Unoson, Cecilia
    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.
    The toxin-antitoxin system tisB-istR1 Expression, regulation and biological role in persister phenotypes2012In: RNA Biology, ISSN 1547-6286, E-ISSN 1555-8584, Vol. 9, no 12, p. 1513-1519Article, review/survey (Refereed)
    Abstract [en]

    Chromosomally encoded toxin-antitoxin (TA) systems are abundantly present in bacteria and archaea. They have become a hot topic in recent years, because-after many frustrating years of searching for biological functions-some are now known to play roles in persister formation. Persisterscells represent a subset of a bacterial population that enters a dormant state and thus becomes refractory to the action of antibiotics. TA modules come in several different flavors, regarding the nature of their gene products, their molecular mechanisms of regulation, their cellular targets, and probably their role in physiology. This review will primarily focus on the SOS-associated tisB/istR1 system in Escherichia coli and discuss its nuts and bolts as well as its effect in promoting a subpopulation phenotype that likely benefits long-term survival of a stressed population.

  • 212.
    Walldén, Mats
    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.
    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.
    Studying transcriptional interactions in single cells at sufficient resolution2011In: Current Opinion in Biotechnology, ISSN 0958-1669, E-ISSN 1879-0429, Vol. 22, no 1, p. 81-86Article, review/survey (Refereed)
    Abstract [en]

    Our ability to dissect and understand the principles of gene regulatory circuits is partly limited by the resolution of our experimental assays. In this brief review, we discuss aspects of gene expression in microbial organisms apparent only when increasing the experimental resolution from populations to single cells and sub-cellular structures, from snap-shots to high-speed time-lapse movies and from molecular ensembles to single molecules.

  • 213.
    Walldén, Mats
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Fange, David
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Gustaf, Ullman
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Marklund, Erik G
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Elf, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Fluctuations in replication initiation determine the generation time and size distributions of E. coli cellsManuscript (preprint) (Other academic)
  • 214.
    Walldén, Mats
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Fange, David
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lundius, Ebba Gregorsson
    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.
    Baltekin, Özden
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular 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, Molecular Systems Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    The Synchronization of Replication and Division Cycles in Individual E. coli Cells2016In: Cell, ISSN 0092-8674, E-ISSN 1097-4172, Vol. 166, no 3, p. 729-739Article in journal (Refereed)
    Abstract [en]

    Isogenic E. coli cells growing in a constant environment display significant variability in growth rates, division sizes, and generation times. The guiding principle appears to be that each cell, during one generation, adds a size increment that is uncorrelated to its birth size. Here, we investigate the mechanisms underlying this "adder'' behavior by mapping the chromosome replication cycle to the division cycle of individual cells using fluorescence microscopy. We have found that initiation of chromosome replication is triggered at a fixed volume per chromosome independent of a cell's birth volume and growth rate. Each initiation event is coupled to a division event after a growth-rate-dependent time. We formalize our findings in a model showing that cell-to-cell variation in division timing and cell size is mainly driven by variations in growth rate. The model also explains why fast-growing cells display adder behavior and correctly predict deviations from the adder behavior at slow growth.

  • 215.
    Wallin, Göran
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Härd, Torleif
    Åqvist, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Folding-Reaction Coupling in a Self-Cleaving Protein2012In: Journal of Chemical Theory and Computation, ISSN 1549-9618, E-ISSN 1549-9626, Vol. 8, no 10, p. 3871-3879Article in journal (Refereed)
    Abstract [en]

    Backbone torsional strain has been implicated as a cause of rate enhancement in a class of autoprocessing proteins performing proteolysis and protein splicing. In the autoproteolytic protein domain SEA, folding and proteolytic activity have experimentally been shown to be coupled with about 7 kcal/mol of folding free energy available for catalysis. Here, we have examined the catalytic strategy of SEA with molecular dynamics simulations, potential of mean force free energy profiles, and B3LYP/6-311G(d,p) density functional calculations. A quantitative estimate of the free energy stored as protein strain (about 8 kcal/mol), that is available for catalyzing the cleavage reaction, is obtained and found to be in excellent agreement with thermodynamic and kinetic data. It is further shown that there is strong coupling between folding and reaction coordinates leading to reactant state destabilization in the direction of folding and transition state stabilization along the reaction coordinate. This situation is different from the preorganized active site model in that the fully folded transition state stabilizing structure is not realized until the reaction barrier is surmounted.

  • 216.
    Wallin, Göran
    et al.
    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.
    Åqvist, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Energetics of activation of GTP hydrolysis on the ribosome2013In: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 4, p. 1733-Article in journal (Refereed)
    Abstract [en]

    Several of the steps in protein synthesis on the ribosome utilize hydrolysis of guanosine triphosphate (GTP) as the driving force. This reaction is catalyzed by translation factors that become activated upon binding to the ribosome. The recently determined crystal structure of an elongation factor-Tuternary complex bound to the ribosome allows the energetics of GTP activation to be explored by computer simulations. A central problem regards the role of the universally conserved histidine, which has been proposed to act as a general base for guanosine triphosphate hydrolysis. Here we report a detailed energetic and structural analysis of different possible protonation states that could be involved in activation of the reaction. We show that the histidine cannot act as a general base, but must be protonated and in its active conformation to promote GTP hydrolysis. We further show that the sarcin-ricin loop of the ribosome spontaneously drives the histidine into the correct conformation for GTP activation.

  • 217. Wang, F
    et al.
    Weckert, E
    Ziaja, B
    Center for Free-Electron Laser Science, Deutsches Elektronen-Synchrotron, Notkestrasse 85, D-22607 Hamburg, Germany.
    Larsson, Daniel S.D.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Van der spoel, David
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Coherent Diffraction of a Single Virus Particle : The Impact of a Water Layer on the Available Orientational Information2011In: 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)
    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.

  • 218.
    Wang, Siyang
    et al.
    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.
    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.
    Hellander, Stefan
    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.
    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.
    Stochastic reaction–diffusion processes with embedded lower dimensional structures2012Report (Other academic)
  • 219.
    Wang, Siyang
    et al.
    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.
    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.
    Hellander, Stefan
    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.
    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.
    Stochastic reaction–diffusion processes with embedded lower-dimensional structures2014In: Bulletin of Mathematical Biology, ISSN 0092-8240, E-ISSN 1522-9602, Vol. 76, p. 819-853Article in journal (Refereed)
  • 220.
    Wang, Yaofeng
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Larsson, Daniel S D
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    van der Spoel, David
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Encapsulation of myoglobin in a cetyl trimethylammonium bromide micelle in vacuo: a simulation study2009In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 48, no 5, p. 1006-1015Article in journal (Refereed)
    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.

  • 221.
    Webster, Matthew T.
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Kamgari, Nona
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Perloski, Michele
    Höppner, Marc P.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Axelsson, Erik
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Hedhammar, Ake
    Pielberg, Gerli
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lindblad-Toh, Kerstin
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Linked genetic variants on chromosome 10 control ear morphology and body mass among dog breeds2015In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 16, article id 474Article in journal (Refereed)
    Abstract [en]

    Background: The domestic dog is a rich resource for mapping the genetic components of phenotypic variation due to its unique population history involving strong artificial selection. Genome-wide association studies have revealed a number of chromosomal regions where genetic variation associates with morphological characters that typify dog breeds. A region on chromosome 10 is among those with the highest levels of genetic differentiation between dog breeds and is associated with body mass and ear morphology, a common motif of animal domestication. We characterised variation in this region to uncover haplotype structure and identify candidate functional variants. Results: We first identified SNPs that strongly associate with body mass and ear type by comparing sequence variation in a 3 Mb region between 19 breeds with a variety of phenotypes. We next genotyped a subset of 123 candidate SNPs in 288 samples from 46 breeds to identify the variants most highly associated with phenotype and infer haplotype structure. A cluster of SNPs that associate strongly with the drop ear phenotype is located within a narrow interval downstream of the gene MSRB3, which is involved in human hearing. These SNPs are in strong genetic linkage with another set of variants that correlate with body mass within the gene HMGA2, which affects human height. In addition we find evidence that this region has been under selection during dog domestication, and identify a cluster of SNPs within MSRB3 that are highly differentiated between dogs and wolves. Conclusions: We characterise genetically linked variants that potentially influence ear type and body mass in dog breeds, both key traits that have been modified by selective breeding that may also be important for domestication. The finding that variants on long haplotypes have effects on more than one trait suggests that genetic linkage can be an important determinant of the phenotypic response to selection in domestic animals.

  • 222.
    Wennberg, Christian L.
    et al.
    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.
    Hub, Jochen S.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Large Influence of Cholesterol on Solute Partitioning into Lipid Membranes2012In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 134, no 11, p. 5351-5361Article in journal (Refereed)
    Abstract [en]

    Cholesterol plays an important role in maintaining the correct fluidity and rigidity of the plasma membrane of all animal cells, and hence, it is present in concentrations ranging from 20 to 50 mol %. Whereas the effect of cholesterol on such mechanical properties has been studied exhaustively over the last decades, the structural basis for cholesterol effects on membrane permeability is still unclear. Here we apply systematic molecular dynamics simulations to study the partitioning of solutes between water and membranes. We derive potentials of mean force for six different solutes permeating across 20 different lipid membranes containing one out of four types of phospholipids plus a cholesterol content varying from 0 to 50 mol %. Surprisingly, cholesterol decreases solute partitioning into the lipid tail region of the membranes much more strongly than expected from experiments on macroscopic membranes, suggesting that a laterally inhomogeneous cholesterol concentration and permeability may be required to explain experimental findings. The simulations indicate that the cost of breaking van der Waals interactions between the lipid tails of cholesterol-containing membranes account for the reduced partitioning rather than the surface area per phospholipid, which has been frequently suggested as a determinant for solute partitioning. The simulations further show that the partitioning is more sensitive to cholesterol (i) for larger solutes, (ii) in membranes with saturated as compared to membranes with unsaturated lipid tails, and (iii) in membranes with smaller lipid head groups.

  • 223. Wennberg, Christian L.
    et al.
    Zocher, Florian
    Van der Spoel, David
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Pohl, Peter
    Hub, Jochen S.
    Unexpected Effects of Cholesterol on Membrane Permeability2013In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 104, no 2, p. 192A-193AArticle in journal (Other academic)
  • 224. Willander, Hanna
    et al.
    Askarieh, Glareh
    Landreh, Michael
    Westermark, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Nordling, Kerstin
    Keränen, Henrik
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Hermansson, Erik
    Hamvas, Aaron
    Nogee, Lawrence M.
    Bergman, Tomas
    Saenz, Alejandra
    Casals, Cristina
    Åqvist, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Jörnvall, Hans
    Berglund, Helena
    Presto, Jenny
    Department of Anatomy, Physiology, and Biochemistry, Swedish University of Agricultural Sciences, S-751 24 Uppsala, Sweden.
    Knight, Stefan D.
    Department of Molecular Biology, Swedish University of Agricultural Sciences, S-751 24 Uppsala, Sweden;.
    Johansson, Jan
    High-resolution structure of a BRICHOS domain and its implications for anti-amyloid chaperone activity on lung surfactant protein C2012In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 109, no 7, p. 2325-2329Article in journal (Refereed)
    Abstract [en]

    BRICHOS domains are encoded in >30 human genes, which are associated with cancer, neurodegeneration, and interstitial lung disease (ILD). The BRICHOS domain from lung surfactant protein C proprotein (proSP-C) is required for membrane insertion of SP-C and has anti-amyloid activity in vitro. Here, we report the 2.1 angstrom crystal structure of the human proSP-C BRICHOS domain, which, together with molecular dynamics simulations and hydrogen-deuterium exchange mass spectrometry, reveals how BRICHOS domains may mediate chaperone activity. Observation of amyloid deposits composed of mature SP-C in lung tissue samples from ILD patients with mutations in the BRICHOS domain or in its peptide-binding linker region supports the in vivo relevance of the proposed mechanism. The results indicate that ILD mutations interfering with proSP-C BRICHOS activity cause amyloid disease secondary to intramolecular chaperone malfunction.

  • 225.
    Xu, Bo
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Fällmar, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Boukharta, Lars
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Pruner, Jasna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Lundell, Ingrid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Mohell, Nina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Gutiérrez-de-Terán, Hugo
    Åqvist, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Larhammar, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
    Mutagenesis and Computational Modeling of Human G‑Protein-Coupled Receptor Y2 for Neuropeptide Y and Peptide YY2013In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 52, no 45, p. 7987-7998Article in journal (Refereed)
    Abstract [en]

    Neuropeptide Y and peptide YY receptor type 2 (Y2) is involved in appetite regulation and several other physiological processes. We have investigated the structure of the human Y2 receptor. Computational modeling of receptor–agonist interactions was used as a guide to design a series of receptor mutants, followed by binding assays using full-length and truncated peptide agonists and the Y2-specific antagonist BIIE0246. Our model suggested a hydrogen bond network among highly conserved residues Thr2.61, Gln3.32, and His7.39, which could play roles in ligand binding and/or receptor structure. In addition, the C-terminus of the peptide could make contact with residues Tyr5.38 and Leu6.51. Mutagenesis of all these positions, followed by binding assays, provides experimental support for our computational model: most of the mutants for the residues forming the proposed hydrogen bond network displayed reduced peptide agonist affinities as well as reduced hPYY3-36 potency in a functional assay. The Ala and Leu mutants of Gln3.32 and His7.39 disrupted membrane expression of the receptor. Combined with the modeling, the experimental results support roles for these hydrogen bond network residues in peptide binding as well as receptor architecture. The reduced agonist affinity for mutants of Tyr5.38 and Leu6.51 supports their role in a binding pocket surrounding the invariant tyrosine at position 36 of the peptide ligands. The results for antagonist BIIE0246 suggest several differences in interactions compared to those of the peptides. Our results lead to a new structural model for NPY family receptors and peptide binding.

  • 226. Yang, Hongqian
    et al.
    Good, David M.
    van der Spoel, David
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Zubarev, Roman A.
    Carbonyl Charge Solvation Patterns May Relate to Fragmentation Classes in Collision-Activated Dissociation2012In: Journal of the American Society for Mass Spectrometry, ISSN 1044-0305, E-ISSN 1879-1123, Vol. 23, no 8, p. 1319-1325Article in journal (Refereed)
    Abstract [en]

    Here, we investigate the hypothesis that the origin of Class I fragmentation in tryptic peptide dications corresponding to the cleavage of the first two amino acids from the N-terminus is due to a dominant charge solvation pattern. Molecular dynamics simulations (MDS) of model A(n)R dications confirmed the existence of a persistent solvation of the protonated N-terminus on the second backbone carbonyl. Additionally, MDS predicted a new distinct fragmentation class corresponding to the loss of two amino acids from the C-terminus. This prediction was confirmed experimentally at very low excitation levels. The pattern produced by electron transfer dissociation of the same dications gave markedly decreased cleavage frequencies at the second peptide bond, which, within the non-local fragmentation mechanism, supports the preferential charge solvation on the second carbonyl. Taken together, these results confirm the role of a charge solvation pattern in the origin of fragmentation classes.

  • 227.
    Zhang, Haiyang
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Ge, Chunling
    van der Spoel, David
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Feng, Wei
    Tan, Tianwei
    Insight into the Structural Deformations of Beta-Cyclodextrin Caused by Alcohol Cosolvents and Guest Molecules2012In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 116, no 12, p. 3880-3889Article in journal (Refereed)
    Abstract [en]

    Beta-cyclodextrin (beta-CD) is an ideal candidate for a host molecule, and it is used as such in drug delivery and separation technology. The structural behavior of free beta-CD and host guest complexes of beta-CD with two isoflavonoid isomers (puerarin and daidzin) in aqueous alcohol solutions, covering methanol, ethanol, 2-propanol, and 1-propanol, was investigated through molecular dynamics (MD) simulations. The MD results highlighted aspects of the structural flexibility and rigidity of beta-CD in different alcohol solutions. The alcohol residence time within the beta-CD cavity, solvent distribution around beta-CD, and guest-induced structural changes were analyzed. Interaction with puerarin endowed beta-CD with a more rigid structure than with daidzin and a weaker ternary complex beta-CD/puerarin/alcohol was formed with a local participation of water molecules. The retention behavior of puerarin and daidzin on a beta-CD-coupled medium was determined via chromatographic experiments and simulation results provided a structural explanation for such interactions.

  • 228.
    Zhang, Haiyang
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Tan, Tianwei
    Hetenyi, Csaba
    Lv, Yongqin
    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.
    Cooperative Binding of Cyclodextrin Dimers to Isoflavone Analogues Elucidated by Free Energy Calculations2014In: The Journal of Physical Chemistry C, ISSN 1932-7447, E-ISSN 1932-7455, Vol. 118, no 13, p. 7163-7173Article in journal (Refereed)
    Abstract [en]

    Dimerization of cyclodextrin (CD) molecules is an elementary step in the construction of CD-based nanostructured materials. Cooperative binding of CD cavities to guest molecules facilitates the dimerization process and, consequently, the overall stability and assembly of CD nanostructures. In the present study, all three dimerization modes (head-to-head, head-to-tail, and tail-to-tail) of beta-CD molecules and their binding to three isoflavone drug analogues (puerarin, daidzin, and daidzein) were investigated in explicit water surrounding using molecular dynamics simulations. Total and individual contributions from the binding partners and solvent environment to the thermodynamics of these binding reactions are quantified in detail using free energy calculations. Cooperative drug binding to two CD cavities gives an enhanced binding strength for daidzin and daidzein, whereas for puerarin no obvious enhancement is observed. Head-tohead dimerization yields the most stable complexes for inclusion of the tested isoflavones (templates) and may be a promising building block for construction of template-stabilized CD nanostructures. Compared to the case of CD monomers, the desolvation of CD dimers and entropy changes upon complexation prove to be influential factors of cooperative binding. Our results shed light on key points of the design of CDbased supramolecular assemblies. We also show that structure-based calculation of binding thermodynamics can quantify stabilization caused by cooperative effects in building blocks of nanostructured materials.

  • 229.
    Zhang, Haiyang
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Tan, Tianwei
    Hetenyi, Csaba
    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.
    Quantification of Solvent Contribution to the Stability of Noncovalent Complexes2013In: Journal of Chemical Theory and Computation, ISSN 1549-9618, E-ISSN 1549-9626, Vol. 9, no 10, p. 4542-4551Article in journal (Refereed)
    Abstract [en]

    We introduce an indirect approach to estimate the solvation contributions to the thermodynamics of noncovalent complex formation through molecular dynamics simulation. This estimation is demonstrated by potential of mean force and entropy calculations on the binding process between beta-cyclodextrin (host) and four drug molecules puerarin, daidzin, daidzein, and nabumetone (guest) in explicit water, followed by a stepwise extraction of individual enthalpy (Delta H) and entropy (Delta S) terms from the total free energy. Detailed analysis on the energetics of the host-guest complexation demonstrates that flexibility of the binding partners and solvation-related Delta H and Delta S need to be included explicitly for accurate estimation of the binding thermodynamics. From this, and our previous work on the solvent dependency of binding energies (Zhang et al. J. Phys. Chem. B 2012, 116, 12684-12693), it follows that calculations neglecting host or guest flexibility, or those employing implicit solvent, will not be able to systematically predict binding free energies. The approach presented here can be readily adopted for obtaining a deeper understanding of the mechanisms governing noncovalent associations in solution.

  • 230.
    Zhang, Haiyang
    et al.
    Univ Sci & Technol Beijing, Sch Chem & Biol Engn, Dept Biol Sci & Engn, Beijing 100083, Peoples R China.;Beijing Univ Chem Technol, Dept Biochem Engn, Beijing Key Lab Bioproc, Beijing 100029, Peoples R China..
    Tan, Tianwei
    Beijing Univ Chem Technol, Dept Biochem Engn, Beijing Key Lab Bioproc, Beijing 100029, Peoples R China..
    Van der Spoel, David
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Generalized Born and Explicit Solvent Models for Free Energy Calculations in Organic Solvents: Cyclodextrin Dimerization2015In: Journal of Chemical Theory and Computation, ISSN 1549-9618, E-ISSN 1549-9626, Vol. 11, no 11, p. 5103-5113Article in journal (Refereed)
    Abstract [en]

    Evaluation of solvation (binding) free energies with implicit solvent models in different dielectric environments for biological simulations as well as high throughput ligand screening remain challenging endeavors. In order to address how well implicit solvent models approximate explicit ones we examined four generalized Born models (GB(still), GB(HCT), GB(OBC)I, and GB(OBC)II) for determining the dimerization free energy (Delta G(0)) of beta-cyclodextrin monomers in 17 implicit solvents with dielectric constants (D) ranging from 5 to 80 and compared the results to previous free energy calculations with explicit solvents (Zhang et al. J. Phys. Chem. B 2012, 116, 12684-12693). The comparison indicates that neglecting the environmental dependence of Born radii appears acceptable for such calculations involving cyclodextrin and that the GB(still) and GB(OBC)I models yield a reasonable estimation of Delta G(0), although the details of binding are quite different from explicit solvents. Large discrepancies between implicit and explicit solvent models occur in high-dielectric media with strong hydrogen bond (HB) interruption properties. Delta G(0) with the GB models is shown to correlate strongly to 2(D-1)/(2D+1) (R-2 similar to 0.90) in line with the Onsager reaction field (Onsager J. Am. Chem. Soc. 1936, 58, 1486-1493) but to be very sensitive to D (D < 10) as well. Both high-dielectric environments where hydrogen bonds are of interest and low-dielectric media such as protein binding pockets and membrane interiors therefore need to be considered with caution in GB-based calculations. Finally, a literature analysis of Gibbs energy of solvation of small molecules in organic liquids shows that the Onsager relation does not hold for real molecules since the correlation between Delta G(0) and 2(D-1)/(2D+1) is low for most solutes. Interestingly, explicit solvent calculations of the solvation free energy (Zhang et al. J. Chem. Inf. Model. 2015, SS, 1192-1201) reproduce the weak experimental correlations with 2(D-1)/(2D+1) very well.

  • 231.
    Zhang, Jin
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Tuguldur, Badamkhatan
    Uppsala University, Science for Life Laboratory, SciLifeLab. 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. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Force Field Benchmark of Organic Liquids. 2. Gibbs Energy of Solvation2015In: JOURNAL OF CHEMICAL INFORMATION AND MODELING, ISSN 1549-9596, Vol. 55, no 6, p. 1192-1201Article in journal (Refereed)
    Abstract [en]

    Quantitative prediction of physical properties of liquids is a longstanding goal of molecular simulation. Here, we evaluate the predictive power of the Generalized Amber Force Field (Wang et al. J. Comput. Chem. 2004, 25, 1157-1174) for the Gibbs energy of solvation of organic molecules in organic solvents using the thermodynamics integration (TI) method. The results are compared to experimental data, to a model based on quantitative structure property relations (QSPR), and to the conductor-like screening models for realistic solvation (COSMO-RS) model. Although the TI calculations yield slightly better correlation to experimental results than the other models, in all fairness we should conclude that the difference between the models is minor since both QSPR and COSMO-RS yield a slightly lower RMSD from that of the experiment (<3.5 kJ/mol). By analyzing which molecules (either as solvents or solutes) are outliers in the TI calculations, we can pinpoint where additional parametrization efforts are needed. For the force field based TI calculations, deviations from the experiment occur in particular when compounds containing nitro or ester groups are solvated into other liquids, suggesting that the interaction between these groups and solvents may be too strong. In the COSMO-RS calculations, outliers mainly occur when compounds containing (in particular aromatic) rings are solvated despite using a ring correction term in the calculations.

  • 232.
    Zhang, Jingji
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology.
    Ieong, Ka-Weng
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology.
    Johansson, Magnus
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Ehrenberg, Måns
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology.
    Accuracy of initial codon selection by aminoacyl-tRNAs on the mRNA-programmed bacterial ribosome2015In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 112, no 31, p. 9602-9607Article in journal (Refereed)
    Abstract [en]

    We used a cell-free system with pure Escherichia coli components to study initial codon selection of aminoacyl-tRNAs in ternary complex with elongation factor Tu and GTP on messenger RNA-programmed ribosomes. We took advantage of the universal rate-accuracy trade-off for all enzymatic selections to determine how the efficiency of initial codon readings decreased linearly toward zero as the accuracy of discrimination against near-cognate and wobble codon readings increased toward the maximal asymptote, the d value. We report data on the rate-accuracy variation for 7 cognate, 7 wobble, and 56 near-cognate codon readings comprising about 15% of the genetic code. Their d values varied about 400-fold in the 200-80,000 range depending on type of mismatch, mismatch position in the codon, and tRNA isoacceptor type. We identified error hot spots (d = 200) for U:G misreading in second and U:U or G:A misreading in third codon position by His-tRNA(His) and, as also seen in vivo, Glu-tRNA(Glu). We suggest that the proofreading mechanism has evolved to attenuate error hot spots in initial selection such as those found here.

  • 233.
    Zhang, Jingji
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology.
    Ieong, Ka-Weng
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology.
    Johansson, Magnus
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Ehrenberg, Måns
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology.
    Large accuracy variation in initial codon selection by aminoacyl-tRNAs on the bacterial ribosomeManuscript (preprint) (Other academic)
  • 234.
    Zhang, Wei
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
    Dourado, Daniel F. A. R.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Mannervik, Bengt
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Biochemistry.
    Evolution of the active site of human glutathione transferase A2-2 for enhanced activity with dietary isothiocyanates2015In: Biochimica et Biophysica Acta - General Subjects, ISSN 0304-4165, E-ISSN 1872-8006, Vol. 1850, no 4, p. 742-749Article in journal (Refereed)
    Abstract [en]

    Background: Organic isothiocyanates (ITCs) are produced by plants, in which they are released from glucosinolates by myrosinase. ITCs are generally toxic and serve as a chemical defense against herbivorous insects and against infections by microorganisms. In mammalian tissues subtoxic concentrations of ITCs can provide protective effects against cancer and other diseases partially by induction of glutathione transferases (GSTs) and other detoxication enzymes. Thus, human consumption of edible plants rich in ITCs is presumed to provide health benefits. ITCs react with intracellular glutathione to form dithiocarbamates, catalyzed by GSTs. Formation of glutathione conjugates is central to the biotransformation of ITCs and leads to a route for their excretion. Clearly, the emergence of ITC conjugating activity in GSTs is essential from the biological and evolutionary perspective. Methods: In the present investigation an active-site-focused mutant library of GST A2-2 has been screened for enzyme variants with enhanced ITC activity. Results: Significantly superior activities were found in 34 of the approximately 2000 mutants analyzed, and the majority of the superior GSTs featured His and Gly residues in one of the three active-site positions subjected to mutagenesis. Conclusions: We explored the propensity of GSTs to obtain altered substrate selectivity and moreover, identified a specific pattern of mutagenesis in GST for enhanced PEITC detoxification, which may play an important role in the evolution of adaptive responses in organisms subjected to ITCs. General significance: The facile acquisition of enhanced ITC activity demonstrates that this important detoxication function can be promoted by numerous evolutionary trajectories in sequence space. (C) 2014 Elsevier B.V. All rights reserved.

  • 235.
    Zocher, Florian
    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
    Pohl, Peter
    Hub, Jochen S.
    Local Partition Coefficients Govern Solute Permeability of Cholesterol-Containing Membranes2013In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 105, no 12, p. 2760-2770Article in journal (Refereed)
    Abstract [en]

    The permeability of lipid membranes for metabolic molecules or drugs is routinely estimated from the solute's oil/water partition coefficient. However, the molecular determinants that modulate the permeability in different lipid compositions have remained unclear. Here, we combine scanning electrochemical microscopy and molecular-dynamics simulations to study the effect of cholesterol on membrane permeability, because cholesterol is abundant in all animal membranes. The permeability of membranes from natural lipid mixtures to both hydrophilic and hydrophobic solutes monotonously decreases with cholesterol concentration [Chol]. The same is true for hydrophilic solutes and planar bilayers composed of dioleoyl-phosphatidylcholine or dioleoyl-phosphatidyl-ethanolamine. However, these synthetic lipids give rise to a bell-shaped dependence of membrane permeability on [Chol] for very hydrophobic solutes. The simulations indicate that cholesterol does not affect the diffusion constant inside the membrane. Instead, local partition coefficients at the lipid headgroups and at the lipid tails are modulated oppositely by cholesterol, explaining the experimental findings. Structurally, these modulations are induced by looser packing at the lipid headgroups and tighter packing at the tails upon the addition of cholesterol.

  • 236.
    Åqvist, Johan
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
    Kamerlin, Lynn Shina Caroline
    The Conformation of a Catalytic Loop Is Central to GTPase Activity on the Ribosome2015In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 54, no 2, p. 546-556Article in journal (Refereed)
    Abstract [en]

    The translational GTPases hydrolyze GTP on the ribosome at several stages of the protein synthesis cycle. Because of the strong conservation of their catalytic center, these enzymes are expected to operate through a universal hydrolysis mechanism, in which a critical histidine residue together with the sarcin-ricin loop of the large ribosomal subunit is necessary for GTPase activation. Here we examine different possible pathways for GTP hydrolysis by EF-Tu through extensive computer simulations. We show that a conformational change of the peptide plane preceding this histidine has a decisive effect on the energetics of the reaction. This transition was predicted earlier by us and has recently been confirmed experimentally. It is found to promote early proton transfer from water to the gamma-phosphate group of GTP, followed by nucleophilic attack by hydroxide ion. The calculated reaction energetics is in good agreement with available kinetic data, for both wild-type and mutant versions of EF-Tu, and indicates that the latter may enforce a change in mechanism toward more concerted pathways.

2345 201 - 236 of 236
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf