Publications by authors named "Matthieu Chavent"

28 Publications

  • Page 1 of 1

Visualizing protein structures - tools and trends.

Biochem Soc Trans 2020 04;48(2):499-506

Laboratoire de Biochimie Théorique, CNRS, Université de Paris, UPR 9080, 13 rue Pierre et Marie Curie, F-75005, Paris, France.

Molecular visualization is fundamental in the current scientific literature, textbooks and dissemination materials. It provides an essential support for presenting results, reasoning on and formulating hypotheses related to molecular structure. Tools for visual exploration of structural data have become easily accessible on a broad variety of platforms thanks to advanced software tools that render a great service to the scientific community. These tools are often developed across disciplines bridging computer science, biology and chemistry. This mini-review was written as a short and compact overview for scientists who need to visualize protein structures and want to make an informed decision which tool they should use. Here, we first describe a few 'Swiss Army knives' geared towards protein visualization for everyday use with an existing large user base, then focus on more specialized tools for peculiar needs that are not yet as broadly known. Our selection is by no means exhaustive, but reflects a diverse snapshot of scenarios that we consider informative for the reader. We end with an account of future trends and perspectives.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1042/BST20190621DOI Listing
April 2020

Structural Basis of Teneurin-Latrophilin Interaction in Repulsive Guidance of Migrating Neurons.

Cell 2020 01 9;180(2):323-339.e19. Epub 2020 Jan 9.

Department of Biochemistry, Oxford University, Oxford OX1 3QU, UK. Electronic address:

Teneurins are ancient metazoan cell adhesion receptors that control brain development and neuronal wiring in higher animals. The extracellular C terminus binds the adhesion GPCR Latrophilin, forming a trans-cellular complex with synaptogenic functions. However, Teneurins, Latrophilins, and FLRT proteins are also expressed during murine cortical cell migration at earlier developmental stages. Here, we present crystal structures of Teneurin-Latrophilin complexes that reveal how the lectin and olfactomedin domains of Latrophilin bind across a spiraling beta-barrel domain of Teneurin, the YD shell. We couple structure-based protein engineering to biophysical analysis, cell migration assays, and in utero electroporation experiments to probe the importance of the interaction in cortical neuron migration. We show that binding of Latrophilins to Teneurins and FLRTs directs the migration of neurons using a contact repulsion-dependent mechanism. The effect is observed with cell bodies and small neurites rather than their processes. The results exemplify how a structure-encoded synaptogenic protein complex is also used for repulsive cell guidance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cell.2019.12.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6978801PMC
January 2020

The conical shape of DIM lipids promotes infection of macrophages.

Proc Natl Acad Sci U S A 2019 12 22;116(51):25649-25658. Epub 2019 Nov 22.

Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, Université Paul Sabatier, 31400 Toulouse, France;

Phthiocerol dimycocerosate (DIM) is a major virulence factor of the pathogen (). While this lipid promotes the entry of into macrophages, which occurs via phagocytosis, its molecular mechanism of action is unknown. Here, we combined biophysical, cell biology, and modeling approaches to reveal the molecular mechanism of DIM action on macrophage membranes leading to the first step of infection. Matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry showed that DIM molecules are transferred from the envelope to macrophage membranes during infection. Multiscale molecular modeling and P-NMR experiments revealed that DIM adopts a conical shape in membranes and aggregates in the stalks formed between 2 opposing lipid bilayers. Infection of macrophages pretreated with lipids of various shapes uncovered a general role for conical lipids in promoting phagocytosis. Taken together, these results reveal how the molecular shape of a mycobacterial lipid can modulate the biological response of macrophages.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.1910368116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6926010PMC
December 2019

Molecular Graphics: Bridging Structural Biologists and Computer Scientists.

Structure 2019 11 26;27(11):1617-1623. Epub 2019 Sep 26.

Institut de Pharmacologie et de Biologie Structurale IPBS, Université de Toulouse, CNRS, UPS, Toulouse, France. Electronic address:

Visualization of molecular structures is one of the most common tasks carried out by structural biologists, typically using software, such as Chimera, COOT, PyMOL, or VMD. In this Perspective article, we outline how past developments in computer graphics and data visualization have expanded the understanding of biomolecular function, and we summarize recent advances that promise to further transform structural biology. We also highlight how progress in molecular graphics has been impeded by communication barriers between two communities: the computer scientists driving these advances, and the structural and computational biologists who stand to benefit. By pointing to canonical papers and explaining technical progress underlying new graphical developments in simple terms, we aim to improve communication between these communities; this, in turn, would help shape future developments in molecular graphics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.str.2019.09.001DOI Listing
November 2019

Sharing Data from Molecular Simulations.

J Chem Inf Model 2019 10 11;59(10):4093-4099. Epub 2019 Oct 11.

Science for Life Laboratory, Department of Applied Physics , KTH Royal Institute of Technology , Box 1031, SE-171 21 Solna , Sweden.

Given the need for modern researchers to produce open, reproducible scientific output, the lack of standards and best practices for sharing data and workflows used to produce and analyze molecular dynamics (MD) simulations has become an important issue in the field. There are now multiple well-established packages to perform molecular dynamics simulations, often highly tuned for exploiting specific classes of hardware, each with strong communities surrounding them, but with very limited interoperability/transferability options. Thus, the choice of the software package often dictates the workflow for both simulation production and analysis. The level of detail in documenting the workflows and analysis code varies greatly in published work, hindering reproducibility of the reported results and the ability for other researchers to build on these studies. An increasing number of researchers are motivated to make their data available, but many challenges remain in order to effectively share and reuse simulation data. To discuss these and other issues related to best practices in the field in general, we organized a workshop in November 2018 ( https://bioexcel.eu/events/workshop-on-sharing-data-from-molecular-simulations/ ). Here, we present a brief overview of this workshop and topics discussed. We hope this effort will spark further conversation in the MD community to pave the way toward more open, interoperable, and reproducible outputs coming from research studies using MD simulations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jcim.9b00665DOI Listing
October 2019

Cholesterol Interaction Sites on the Transmembrane Domain of the Hedgehog Signal Transducer and Class F G Protein-Coupled Receptor Smoothened.

Structure 2019 03 27;27(3):549-559.e2. Epub 2018 Dec 27.

Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK. Electronic address:

Transduction of Hedgehog signals across the plasma membrane is facilitated by the class F G-protein-coupled-receptor (GPCR) Smoothened (SMO). Recent studies suggest that SMO is modulated via interactions of its transmembrane (TM) domain with cholesterol. We apply molecular dynamics simulations of SMO embedded in cholesterol containing lipid bilayers, revealing a direct interaction of cholesterol with the TM domain at regions distinct from those observed in class A GPCRs. In particular the extracellular tips of helices TM2 and TM3 form a well-defined cholesterol interaction site. Potential of mean force calculations yield a free energy landscape for cholesterol binding. Alongside analysis of equilibrium cholesterol occupancy, this reveals the existence of a dynamic "greasy patch" interaction with the TM domain of SMO, which may be compared with previously identified lipid interaction sites on other membrane proteins. These predictions provide molecular-level insights into cholesterol interactions with a class F GPCR, suggesting potential druggable sites.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.str.2018.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6408332PMC
March 2019

How nanoscale protein interactions determine the mesoscale dynamic organisation of bacterial outer membrane proteins.

Nat Commun 2018 07 20;9(1):2846. Epub 2018 Jul 20.

Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 5RJ, UK.

The spatiotemporal organisation of membranes is often characterised by the formation of large protein clusters. In Escherichia coli, outer membrane protein (OMP) clustering leads to OMP islands, the formation of which underpins OMP turnover and drives organisation across the cell envelope. Modelling how OMP islands form in order to understand their origin and outer membrane behaviour has been confounded by the inherent difficulties of simulating large numbers of OMPs over meaningful timescales. Here, we overcome these problems by training a mesoscale model incorporating thousands of OMPs on coarse-grained molecular dynamics simulations. We achieve simulations over timescales that allow direct comparison to experimental data of OMP behaviour. We show that specific interaction surfaces between OMPs are key to the formation of OMP clusters, that OMP clusters present a mesh of moving barriers that confine newly inserted proteins within islands, and that mesoscale simulations recapitulate the restricted diffusion characteristics of OMPs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-018-05255-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6054660PMC
July 2018

Interactions of the EphA2 Kinase Domain with PIPs in Membranes: Implications for Receptor Function.

Structure 2018 07 7;26(7):1025-1034.e2. Epub 2018 Jun 7.

Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK. Electronic address:

EphA2 is a member of the receptor tyrosine kinase family. Interactions of the cytoplasmic region of EphA2 with the cell membrane are functionally important and yet remain incompletely characterized. Molecular dynamics simulations combined with biochemical studies reveal the interactions of the transmembrane, juxtamembrane (JM), and kinase domains with the membrane. We describe how the kinase domain is oriented relative to the membrane and how the JM region can modulate this interaction. We highlight the role of phosphatidylinositol phosphates (PIPs) in mediating the interaction of the kinase domain with the membrane and, conversely, how positively charged patches at the kinase surface and in the JM region induce the formation of nanoclusters of PIP molecules in the membrane. Integration of these results with those from previous studies enable computational reconstitution of a near complete EphA2 receptor within a membrane, suggesting a role for receptor-lipid interactions in modulation of EphA2.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.str.2018.05.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6039763PMC
July 2018

Protein crowding and lipid complexity influence the nanoscale dynamic organization of ion channels in cell membranes.

Sci Rep 2017 11 30;7(1):16647. Epub 2017 Nov 30.

Department of Biochemistry, University of Oxford, Oxford, OX1 3QU, UK.

Cell membranes are crowded and complex environments. To investigate the effect of protein-lipid interactions on dynamic organization in mammalian cell membranes, we have performed coarse-grained molecular dynamics simulations containing >100 copies of an inwardly rectifying potassium (Kir) channel which forms specific interactions with the regulatory lipid phosphatidylinositol 4,5-bisphosphate (PIP). The tendency of protein molecules to cluster has the effect of organizing the membrane into dynamic compartments. At the same time, the diversity of lipids present has a marked effect on the clustering behavior of ion channels. Sub-diffusion of proteins and lipids is observed. Protein crowding alters the sub-diffusive behavior of proteins and lipids such as PIP which interact tightly with Kir channels. Protein crowding also affects bilayer properties, such as membrane undulations and bending rigidity, in a PIP-dependent manner. This interplay between the diffusion and the dynamic organization of Kir channels may have important implications for channel function.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-017-16865-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5709381PMC
November 2017

Lipid-Loving ANTs: Molecular Simulations of Cardiolipin Interactions and the Organization of the Adenine Nucleotide Translocase in Model Mitochondrial Membranes.

Biochemistry 2016 Nov 4;55(45):6238-6249. Epub 2016 Nov 4.

Department of Biochemistry, University of Oxford , South Parks Road, Oxford OX1 3QU, U.K.

The exchange of ADP and ATP across the inner mitochondrial membrane is a fundamental cellular process. This exchange is facilitated by the adenine nucleotide translocase, the structure and function of which are critically dependent on the signature phospholipid of mitochondria, cardiolipin (CL). Here we employ multiscale molecular dynamics simulations to investigate CL interactions within a membrane environment. Using simulations at both coarse-grained and atomistic resolutions, we identify three CL binding sites on the translocase, in agreement with those seen in crystal structures and inferred from nuclear magnetic resonance measurements. Characterization of the free energy landscape for lateral lipid interaction via potential of mean force calculations demonstrates the strength of interaction compared to those of binding sites on other mitochondrial membrane proteins, as well as their selectivity for CL over other phospholipids. Extending the analysis to other members of the family, yeast Aac2p and mouse uncoupling protein 2, suggests a degree of conservation. Simulation of large patches of a model mitochondrial membrane containing multiple copies of the translocase shows that CL interactions persist in the presence of protein-protein interactions and suggests CL may mediate interactions between translocases. This study provides a key example of how computational microscopy may be used to shed light on regulatory lipid-protein interactions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.biochem.6b00751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5120876PMC
November 2016

Membrane stiffness is modified by integral membrane proteins.

Soft Matter 2016 Sep;12(37):7792-7803

Department of Biochemistry, University of Oxford, South Parks Rd, Oxford, OX1 3QU, UK.

The ease with which a cell membrane can bend and deform is important for a wide range of biological functions. Peripheral proteins that induce curvature in membranes (e.g. BAR domains) have been studied for a number of years. Little is known, however, about the effect of integral membrane proteins on the stiffness of a membrane (characterised by the bending rigidity, K). We demonstrate by computer simulation that adding integral membrane proteins at physiological densities alters the stiffness of the membrane. First we establish that the coarse-grained MARTINI forcefield is able to accurately reproduce the bending rigidity of a small patch of 1500 phosphatidyl choline lipids by comparing the calculated value to both experiment and an atomistic simulation of the same system. This enables us to simulate the dynamics of large (ca. 50 000 lipids) patches of membrane using the MARTINI coarse-grained description. We find that altering the lipid composition changes the bending rigidity. Adding integral membrane proteins to lipid bilayers also changes the bending rigidity, whilst adding a simple peripheral membrane protein has no effect. Our results suggest that integral membrane proteins can have different effects, and in the case of the bacterial outer membrane protein, BtuB, the greater the density of protein, the larger the reduction in stiffness.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/c6sm01186aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5314686PMC
September 2016

Molecular dynamics simulations of membrane proteins and their interactions: from nanoscale to mesoscale.

Curr Opin Struct Biol 2016 10 21;40:8-16. Epub 2016 Jun 21.

Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK. Electronic address:

Molecular dynamics simulations provide a computational tool to probe membrane proteins and systems at length scales ranging from nanometers to close to a micrometer, and on microsecond timescales. All atom and coarse-grained simulations may be used to explore in detail the interactions of membrane proteins and specific lipids, yielding predictions of lipid binding sites in good agreement with available structural data. Building on the success of protein-lipid interaction simulations, larger scale simulations reveal crowding and clustering of proteins, resulting in slow and anomalous diffusional dynamics, within realistic models of cell membranes. Current methods allow near atomic resolution simulations of small membrane organelles, and of enveloped viruses to be performed, revealing key aspects of their structure and functionally important dynamics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.sbi.2016.06.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5404110PMC
October 2016

Super-complexes of adhesion GPCRs and neural guidance receptors.

Nat Commun 2016 Apr 19;7:11184. Epub 2016 Apr 19.

Department of Biochemistry, Oxford University, Oxford OX1 3QU, UK.

Latrophilin adhesion-GPCRs (Lphn1-3 or ADGRL1-3) and Unc5 cell guidance receptors (Unc5A-D) interact with FLRT proteins (FLRT1-3), thereby promoting cell adhesion and repulsion, respectively. How the three proteins interact and function simultaneously is poorly understood. We show that Unc5D interacts with FLRT2 in cis, controlling cell adhesion in response to externally presented Lphn3. The ectodomains of the three proteins bind cooperatively. Crystal structures of the ternary complex formed by the extracellular domains reveal that Lphn3 dimerizes when bound to FLRT2:Unc5, resulting in a stoichiometry of 1:1:2 (FLRT2:Unc5D:Lphn3). This 1:1:2 complex further dimerizes to form a larger 'super-complex' (2:2:4), using a previously undescribed binding motif in the Unc5D TSP1 domain. Molecular dynamics simulations, point-directed mutagenesis and mass spectrometry demonstrate the stability and molecular properties of these complexes. Our data exemplify how receptors increase their functional repertoire by forming different context-dependent higher-order complexes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ncomms11184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4838878PMC
April 2016

Structures of the EphA2 Receptor at the Membrane: Role of Lipid Interactions.

Structure 2016 Feb 24;24(2):337-47. Epub 2015 Dec 24.

Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK. Electronic address:

Ephs are transmembrane receptors that mediate cell-cell signaling. The N-terminal ectodomain binds ligands and enables receptor clustering, which activates the intracellular kinase. Relatively little is known about the function of the membrane-proximal fibronectin domain 2 (FN2) of the ectodomain. Multiscale molecular dynamics simulations reveal that FN2 interacts with lipid bilayers via a site comprising K441, R443, R465, Q462, S464, S491, W467, F490, and P459-461. FN2 preferentially binds anionic lipids, a preference that is reduced in the mutant K441E + R443E. We confirm these results by measuring the binding of wild-type and mutant FN2 domains to lipid vesicles. In simulations of the complete EphA2 ectodomain plus the transmembrane region, we show that FN2 anchors the otherwise flexible ectodomain at the surface of the bilayer. Altogether, our data suggest that FN2 serves a dual function of interacting with anionic lipids and constraining the structure of the EphA2 ectodomain to adopt membrane-proximal configurations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.str.2015.11.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4744086PMC
February 2016

Molecular Simulations of Gram-Negative Bacterial Membranes: A Vignette of Some Recent Successes.

Biophys J 2015 Aug;109(3):461-8

School of Chemistry, University of Southampton, Southampton, UK. Electronic address:

In the following review we use recent examples from the literature to discuss progress in the area of atomistic and coarse-grained molecular dynamics simulations of selected bacterial membranes and proteins, with a particular focus on Gram-negative bacteria. As structural biology continues to provide increasingly high-resolution data on the proteins that reside within these membranes, simulations have an important role to play in linking these data with the dynamical behavior and function of these proteins. In particular, in the last few years there has been significant progress in addressing the issue of biochemical complexity of bacterial membranes such that the heterogeneity of the lipid and protein components of these membranes are now being incorporated into molecular-level models. Thus, in future we can look forward to complementary data from structural biology and molecular simulations combining to provide key details of structure-dynamics-function relationships in bacterial membranes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bpj.2015.06.050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4571018PMC
August 2015

Supramolecular assemblies underpin turnover of outer membrane proteins in bacteria.

Nature 2015 Jul 10;523(7560):333-6. Epub 2015 Jun 10.

Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.

Gram-negative bacteria inhabit a broad range of ecological niches. For Escherichia coli, this includes river water as well as humans and animals, where it can be both a commensal and a pathogen. Intricate regulatory mechanisms ensure that bacteria have the right complement of β-barrel outer membrane proteins (OMPs) to enable adaptation to a particular habitat. Yet no mechanism is known for replacing OMPs in the outer membrane, an issue that is further confounded by the lack of an energy source and the high stability and abundance of OMPs. Here we uncover the process underpinning OMP turnover in E. coli and show it to be passive and binary in nature, in which old OMPs are displaced to the poles of growing cells as new OMPs take their place. Using fluorescent colicins as OMP-specific probes, in combination with ensemble and single-molecule fluorescence microscopy in vivo and in vitro, as well as molecular dynamics simulations, we established the mechanism for binary OMP partitioning. OMPs clustered to form ∼0.5-μm diameter islands, where their diffusion is restricted by promiscuous interactions with other OMPs. OMP islands were distributed throughout the cell and contained the Bam complex, which catalyses the insertion of OMPs in the outer membrane. However, OMP biogenesis occurred as a gradient that was highest at mid-cell but largely absent at cell poles. The cumulative effect is to push old OMP islands towards the poles of growing cells, leading to a binary distribution when cells divide. Hence, the outer membrane of a Gram-negative bacterium is a spatially and temporally organized structure, and this organization lies at the heart of how OMPs are turned over in the membrane.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nature14461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4905513PMC
July 2015

Nothing to sneeze at: a dynamic and integrative computational model of an influenza A virion.

Structure 2015 Mar 19;23(3):584-597. Epub 2015 Feb 19.

Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK. Electronic address:

The influenza virus is surrounded by an envelope composed of a lipid bilayer and integral membrane proteins. Understanding the structural dynamics of the membrane envelope provides biophysical insights into aspects of viral function, such as the wide-ranging survival times of the virion in different environments. We have combined experimental data from X-ray crystallography, nuclear magnetic resonance spectroscopy, cryo-electron microscopy, and lipidomics to build a model of the intact influenza A virion. This is the basis of microsecond-scale coarse-grained molecular dynamics simulations of the virion, providing simulations at different temperatures and with varying lipid compositions. The presence of the Forssman glycolipid alters a number of biophysical properties of the virion, resulting in reduced mobility of bilayer lipid and protein species. Reduced mobility in the virion membrane may confer physical robustness to changes in environmental conditions. Our simulations indicate that viral spike proteins do not aggregate and thus are competent for multivalent immunoglobulin G interactions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.str.2014.12.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4353694PMC
March 2015

Epock: rapid analysis of protein pocket dynamics.

Bioinformatics 2015 May 12;31(9):1478-80. Epub 2014 Dec 12.

Laboratoire de Biochimie Théorique, CNRS, UPR9080, Univ Paris Diderot, Sorbonne Paris Cité, F-75005 Paris, France and Structural Bioinformatics and Computational Biochemistry Unit, Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK.

Summary: The volume of an internal protein pocket is fundamental to ligand accessibility. Few programs that compute such volumes manage dynamic data from molecular dynamics (MD) simulations. Limited performance often prohibits analysis of large datasets. We present Epock, an efficient command-line tool that calculates pocket volumes from MD trajectories. A plugin for the VMD program provides a graphical user interface to facilitate input creation, run Epock and analyse the results.

Availability And Implementation: Epock C++ source code, Python analysis scripts, VMD Tcl plugin, documentation and installation instructions are freely available at http://epock.bitbucket.org.

Contact: [email protected] or [email protected]

Supplementary Information: Supplementary data are available at Bioinformatics online.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/bioinformatics/btu822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4410650PMC
May 2015

Methodologies for the analysis of instantaneous lipid diffusion in MD simulations of large membrane systems.

Faraday Discuss 2014 17;169:455-75. Epub 2014 Jun 17.

Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, United Kingdom.

Interactions between lipids and membrane proteins play a key role in determining the nanoscale dynamic and structural properties of biological membranes. Molecular dynamics (MD) simulations provide a valuable tool for studying membrane models, complementing experimental approaches. It is now possible to simulate large membrane systems, such as simplified models of bacterial and viral envelope membranes. Consequently, there is a pressing need to develop tools to visualize and quantify the dynamics of these immense systems, which typically comprise millions of particles. To tackle this issue, we have developed visual and quantitative analyses of molecular positions and their velocity field using path line, vector field and streamline techniques. This allows us to highlight large, transient flow-like movements of lipids and to better understand crowding within the lipid bilayer. The current study focuses on visualization and analysis of lipid dynamics. However, the methods are flexible and can be readily applied to e.g. proteins and nanoparticles within large complex membranes. The protocols developed here are readily accessible both as a plugin for the molecular visualization program VMD and as a module for the MDAnalysis library.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/c3fd00145hDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4208077PMC
June 2015

Dimerization of the EphA1 receptor tyrosine kinase transmembrane domain: Insights into the mechanism of receptor activation.

Biochemistry 2014 Oct 17;53(42):6641-52. Epub 2014 Oct 17.

Department of Biochemistry, University of Oxford , South Parks Road, Oxford OX1 3QU, United Kingdom.

EphA1 is a receptor tyrosine kinase (RTK) that plays a key role in developmental processes, including guidance of the migration of axons and cells in the nervous system. EphA1, in common with other RTKs, contains an N-terminal extracellular domain, a single transmembrane (TM) α-helix, and a C-terminal intracellular kinase domain. The TM helix forms a dimer, as seen in recent NMR studies. We have modeled the EphA1 TM dimer using a multiscale approach combining coarse-grain (CG) and atomistic molecular dynamics (MD) simulations. The one-dimensional potential of mean force (PMF) for this system, based on interhelix separation, has been calculated using CG MD simulations. This provides a view of the free energy landscape for helix-helix interactions of the TM dimer in a lipid bilayer. The resulting PMF profiles suggest two states, consistent with a rotation-coupled activation mechanism. The more stable state corresponds to a right-handed helix dimer interacting via an N-terminal glycine zipper motif, consistent with a recent NMR structure (2K1K). A second metastable state corresponds to a structure in which the glycine zipper motif is not involved. Analysis of unrestrained CG MD simulations based on representative models from the PMF calculations or on the NMR structure reveals possible pathways of interconversion between these two states, involving helix rotations about their long axes. This suggests that the interaction of TM helices in EphA1 dimers may be intrinsically dynamic. This provides a potential mechanism for signaling whereby extracellular events drive a shift in the repopulation of the underlying TM helix dimer energy landscape.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/bi500800xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4298228PMC
October 2014

Blind prediction of interfacial water positions in CAPRI.

Proteins 2014 Apr 23;82(4):620-32. Epub 2013 Nov 23.

Interdisciplinary Research Institute USR3078 CNRS, University Lille North of France, Villeneuve d'Ascq, France.

We report the first assessment of blind predictions of water positions at protein-protein interfaces, performed as part of the critical assessment of predicted interactions (CAPRI) community-wide experiment. Groups submitting docking predictions for the complex of the DNase domain of colicin E2 and Im2 immunity protein (CAPRI Target 47), were invited to predict the positions of interfacial water molecules using the method of their choice. The predictions-20 groups submitted a total of 195 models-were assessed by measuring the recall fraction of water-mediated protein contacts. Of the 176 high- or medium-quality docking models-a very good docking performance per se-only 44% had a recall fraction above 0.3, and a mere 6% above 0.5. The actual water positions were in general predicted to an accuracy level no better than 1.5 Å, and even in good models about half of the contacts represented false positives. This notwithstanding, three hotspot interface water positions were quite well predicted, and so was one of the water positions that is believed to stabilize the loop that confers specificity in these complexes. Overall the best interface water predictions was achieved by groups that also produced high-quality docking models, indicating that accurate modelling of the protein portion is a determinant factor. The use of established molecular mechanics force fields, coupled to sampling and optimization procedures also seemed to confer an advantage. Insights gained from this analysis should help improve the prediction of protein-water interactions and their role in stabilizing protein complexes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/prot.24439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4582081PMC
April 2014

Game on, science - how video game technology may help biologists tackle visualization challenges.

PLoS One 2013 6;8(3):e57990. Epub 2013 Mar 6.

Laboratoire de Biochimie Théorique, CNRS, UPR9080, Univ Paris Diderot Sorbonne Paris Cité, Paris, France.

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 the molecular sciences, 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? This approach points to an extension of open computer programs, not only providing access to the source code, but also delivering an easily modifiable and extensible scientific research tool. In this work, we will explore these questions using the Unity3D game engine to develop and prototype a biological network and molecular visualization application for subsequent use in research or education. We have compared several routines to represent spheres and links between them, using either built-in Unity3D features or our own implementation. These developments resulted in a stand-alone viewer capable of displaying molecular structures, surfaces, animated electrostatic field lines and biological networks with powerful, artistic and illustrative rendering methods. We consider this work as a proof of principle demonstrating that the functionalities of classical viewers and more advanced novel features could be implemented in substantially less time and with less development effort. Our prototype is easily modifiable and extensible and may serve others as starting point and platform for their developments. A webserver example, standalone versions for MacOS X, Linux and Windows, source code, screen shots, videos and documentation are available at the address: http://unitymol.sourceforge.net/.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0057990PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3590297PMC
September 2013

Bendix: intuitive helix geometry analysis and abstraction.

Bioinformatics 2012 Aug 23;28(16):2193-4. Epub 2012 Jun 23.

Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.

Unlabelled: The flexibility of α-helices is important for membrane protein function and calls for better visualization and analysis. Software is presented that quantifies and projects the helix axis evolution over time, with the choice of uniform or analytic heatmap graphics according to the local geometry. Bendix supports static, molecular dynamics, atomistic and coarse-grained input.

Availability And Implementation: Bendix source code and documentation, including installation instructions, are freely available at http://sbcb.bioch.ox.ac.uk/Bendix. Bendix is written in Tcl as an extension to VMD and is supported by all major operating systems.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/bioinformatics/bts357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3413393PMC
August 2012

GPU-accelerated atom and dynamic bond visualization using hyperballs: a unified algorithm for balls, sticks, and hyperboloids.

J Comput Chem 2011 Oct 7;32(13):2924-35. Epub 2011 Jul 7.

Laboratoire de Biochimie Théorique, Institut de Biologie Physico-Chimique, CNRS UPR 9080/Université Paris-7, 13, rue Pierre et Marie Curie, F-75005 Paris, France.

Ray casting on graphics processing units (GPUs) opens new possibilities for molecular visualization. We describe the implementation and calculation of diverse molecular representations such as licorice, ball-and-stick, space-filling van der Waals spheres, and approximated solvent-accessible surfaces using GPUs. We introduce HyperBalls, an improved ball-and-stick representation replacing tubes, linking the atom spheres by hyperboloids that can smoothly connect them. This type of depiction is particularly useful to represent dynamic phenomena, such as the evolution of noncovalent bonds. It is furthermore well suited to represent coarse-grained models and spring networks. All these representations can be defined by a single general algebraic equation that is adapted for the ray-casting technique and is well suited for execution on the GPU. Using GPU capabilities, this implementation can routinely, accurately, and interactively render molecules ranging from a few atoms up to huge macromolecular assemblies with more than 500,000 particles. In simple cases, based only on spheres, we have been able to display up to two million atoms smoothly.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jcc.21861DOI Listing
October 2011

GPU-powered tools boost molecular visualization.

Brief Bioinform 2011 Nov 9;12(6):689-701. Epub 2011 Feb 9.

Commissariat à l'énergie atomique et aux énergies alternatives.

Recent advances in experimental structure determination provide a wealth of structural data on huge macromolecular assemblies such as the ribosome or viral capsids, available in public databases. Further structural models arise from reconstructions using symmetry orders or fitting crystal structures into low-resolution maps obtained by electron-microscopy or small angle X-ray scattering experiments. Visual inspection of these huge structures remains an important way of unravelling some of their secrets. However, such visualization cannot conveniently be carried out using conventional rendering approaches, either due to performance limitations or due to lack of realism. Recent developments, in particular drawing benefit from the capabilities of Graphics Processing Units (GPUs), herald the next generation of molecular visualization solutions addressing these issues. In this article, we present advances in computer science and visualization that help biologists visualize, understand and manipulate large and complex molecular systems, introducing concepts that remain little-known in the bioinformatics field. Furthermore, we compile currently available software and methods enhancing the shape perception of such macromolecular assemblies, for example based on surface simplification or lighting ameliorations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/bib/bbq089DOI Listing
November 2011

Biochemical studies and molecular dynamics simulations of Smad3-Erbin interaction identify a non-classical Erbin PDZ binding.

Biochem Biophys Res Commun 2009 Jan 14;378(3):360-5. Epub 2008 Nov 14.

Inserm, U891, Centre de Recherche en Cancérologie de Marseille, Pharmacologie Moléculaire, F-13009 Marseille, France.

In this work, we describe how the Erbin PDZ domain interacts with Smad3, a transductor of the Transforming Growth Factor-beta (TGFbeta) pathway, via its MH2 domain. This interaction was described as important for TGFbeta signaling as it could potentially repress the transcriptional activity of the growth factor. In order to clarify our preliminary experimental observations pointing this interaction, we built a 3D model of the Erbin PDZ/Smad3 MH2 complex and checked its stability using molecular dynamics simulations. This model pointed out charged residues in Smad3 and Erbin which could be important for the interaction. By introducing point mutations of these residues within the proposed binding domains, we experimentally confirmed that arginine 279, glutamic acid 246 in Smad3 and glutamic acid 1321 in Erbin are important for the binding. These data suggest a possible novel interface of binding in the Erbin PDZ domain and reveal an unconventional mode of interaction for a PDZ domain and its ligand.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2008.10.175DOI Listing
January 2009

MetaMol: high-quality visualization of molecular skin surface.

J Mol Graph Model 2008 Sep 29;27(2):209-16. Epub 2008 Apr 29.

Orpailleur Group, Nancy University, Loria, Vandoeuvre les Nancy Cedex, France.

Modeling and visualizing molecular surfaces is an important and challenging task in bioinformatics. Such surfaces play an essential role in better understanding the chemical and physical properties of molecules. However, constructing and displaying molecular surfaces requires complex algorithms. In this article we introduce MetaMol, a new program that generates high-quality images in interactive time. In contrast with existing software that discretizes the surface with triangles or grids, our program is based on a GPU accelerated ray-casting algorithm that directly uses the piecewise-defined algebraic equation of the molecular skin surface. As a result, both better performances and higher quality are obtained.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jmgm.2008.04.007DOI Listing
September 2008

Multiple-step virtual screening using VSM-G: overview and validation of fast geometrical matching enrichment.

J Mol Model 2008 Feb 3;14(2):135-48. Epub 2008 Jan 3.

Nancy Université, LORIA, Groupe ORPAILLEUR, Campus scientifique, BP 239, 54506 Vandoeuvre-lès-Nancy Cedex, France.

Numerous methods are available for use as part of a virtual screening strategy but, as yet, no single method is able to guarantee both a level of confidence comparable to experimental screening and a level of computing efficiency that could drastically cut the costs of early phase drug discovery campaigns. Here, we present VSM-G (virtual screening manager for computational grids), a virtual screening platform that combines several structure-based drug design tools. VSM-G aims to be as user-friendly as possible while retaining enough flexibility to accommodate other in silico techniques as they are developed. In order to illustrate VSM-G concepts, we present a proof-of-concept study of a fast geometrical matching method based on spherical harmonics expansions surfaces. This technique is implemented in VSM-G as the first module of a multiple-step sequence tailored for high-throughput experiments. We show that, using this protocol, notable enrichment of the input molecular database can be achieved against a specific target, here the liver-X nuclear receptor. The benefits, limitations and applicability of the VSM-G approach are discussed. Possible improvements of both the geometrical matching technique and its implementation within VSM-G are suggested.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00894-007-0257-9DOI Listing
February 2008
-->