Matthieu Chavent

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

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/.

Supramolecular assemblies underpin turnover of outer membrane proteins in bacteria

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.

Bendix: intuitive helix geometry analysis and abstraction

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.

Nothing to Sneeze At: A Dynamic and Integrative Computational Model of an Influenza A Virion

Summary 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.

MetaMol: high-quality visualization of molecular skin surface.

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.

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

Graphical abstract

Advances in Human-Protein Interaction - Interactive and Immersive Molecular Simulations

Molecular simulations allow researchers to obtain complementary data with respect to experimental studies and to overcome some of their limitations. Current experimental techniques do not allow to observe the full dynamics of a protein at atomic detail. In return, experiments provide the structures, i.e. the spatial atomic positions, for numerous biomolecular systems, which are often used as starting point for simulation studies. In order to predict, to explain and to understand experimental results, researchers have developed a variety of biomolecular representations and algorithms. They allow to simulate the dynamic behavior of macromolecules at different scales, ranging from detailed models using quantum mechanics or classical molecular mechanics to more approximate representations. These simulations are often controlled a priori by complex and empirical settings. Most researchers visualise the result of their simulation once the computation is finished. Such post-simulation analysis often makes use of specific molecular user interfaces, by reading and visualising the molecular 3D configuration at each step of the simulation. This approach makes it difficult to interact with a simulation in progress. When a problem occurs, or when the researcher does not achieve to observe the predicted behavior, the simulation must be restarted with other settings or constraints. This can result in the waste of an important number of compute cycles, as some simulations last for a long time: several days to weeks may be required to reproduce a short timespan, a few nanoseconds, of molecular reality. Moreover, several biomolecular processes, like folding or large conformational changes of proteins, occur on even longer timescales that are inaccessible to current simulation techniques. It can thus be necessary to impose empirical constraints in order to accelerate a simulation and to reproduce

GPU-powered tools boost molecular visualization

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.

Epock: rapid analysis of protein pocket dynamics.

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: benoist.laurent@gmail.com or baaden@smplinux.de Supplementary information: Supplementary data are available at Bioinformatics online.

Dimerization of the EphA1 Receptor Tyrosine Kinase Transmembrane Domain: Insights into the Mechanism of Receptor Activation

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.