Nicolas Férey

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

Multisensory VR interaction for protein-docking in the CoRSAIRe project

Proteins take on their function in the cell by interacting with other proteins or biomolecular complexes. To study this process, computational methods, collectively named protein docking, are used to predict the position and orientation of a protein ligand when it is bound to a protein receptor or enzyme, taking into account chemical or physical criteria. This process is intensively studied to discover new biological functions for proteins and to better understand how these macromolecules take on these functions at the molecular scale. Pharmaceutical research also employs docking techniques for a variety of purposes, most notably in the virtual screening of large databases of available chemicals to select likely molecular candidates for drug design. The basic hypothesis of our work is that Virtual Reality (VR) and multimodal interaction can increase efficiency in reaching and analysing docking solutions, in addition to fully a computational docking approach. To this end, we conducted an ergonomic analysis of the protein–protein current docking task as it is carried out today. Using these results, we designed an immersive and multimodal application where VR devices, such as the three-dimensional mouse and haptic devices, are used to interactively manipulate two proteins to explore possible docking solutions. During this exploration, visual, audio, and haptic feedbacks are combined to render and evaluate chemical or physical properties of the current docking configuration.

Interactive Molecular Dynamics: Scaling up to Large Systems☆

Combining molecular dynamics simulations with user interaction would have various applications in both education and research. By enabling interactivity the scientist will be able to visualize the experiment in real time and drive the simulation to a desired state more easily. However, interacting with systems of interesting size requires significant computing resources due to the complexity of the simulation. In this paper, we propose an approach to combine a classical parallel molecular dynamics simulator, Gromacs, to a 3D virtual reality environment allowing to steer the simulation through external user forces applied with an haptic device to a selection of atoms. We specifically focused on minimizing the intrusion in the simulator code, on efficient parallel data extraction and filtering to transfer only the necessary data to the visualization environment, and on a controlled asynchronism between various components to improve interactivity. We managed to steer molecular systems of 1.7M atoms at about 25 Hz using 384 CPU cores. This framework allowed us to study a concrete scientific problem by testing one hypothesis of the transport of an iron complex from the exterior of the bacteria to the periplasmic space through the FepA membrane protein.

User needs analysis to design a 3D multimodal protein-docking interface

Protein-Protein docking is a recent practice in biological research which involves using 3D models of proteins to predict the structure of complexes formed by these proteins. Studying protein-protein interactions and how proteins form molecular complexes allows researchers to better understand their function in the cell. Currently, the most common methods used for docking are fully computational approaches, followed by the use of molecular visualization tools to evaluate results. However, these approaches are time consuming and provide a large number of potential solutions. Our basic hypothesis is that a virtual reality (VR) framework for molecular docking can combine the benefits of multimodal rendering, of the biologists expertise in the field of docking, and of automated docking algorithms. We think this approach will increase efficiency in reaching the solution of a docking problem. However designing immersive and multimodal virtual environments (VE) based on VR technology calls for clear and early identification of user needs. To this end, we have analyzed the task of protein-protein docking as it is carried out today, in order to identify benefits and shortcomings of existing tools, and support the design of new interactive paradigms. Using these results, we have defined a new approach and designed a multimodal application for molecular docking in a virtual reality context.

Ten simple rules to create a serious game, illustrated with examples from structural biology

Serious scientific games are games whose purpose is not only fun. In the field of science, the serious goals include crucial activities for scientists: outreach, teaching and research. The number of serious games is increasing rapidly, in particular citizen science games, games that allow people to produce and/or analyze scientific data. Interestingly, it is possible to build a set of rules providing a guideline to create or improve serious games. We present arguments gathered from our own experience ( Phylo , DocMolecules , HiRE-RNA contest and Pangu) as well as examples from the growing literature on scientific serious games.

Dystrophin's central domain forms a complex filament that becomes disorganized by in-frame deletions

Dystrophin, encoded by the DMD gene, is critical for maintaining plasma membrane integrity during muscle contraction events. Mutations in the DMD gene disrupting the reading frame prevent dystrophin production and result in severe Duchenne muscular dystrophy (DMD); in-frame internal deletions allow production of partly functional internally deleted dystrophin and result in less severe Becker muscular dystrophy (BMD). Many known BMD deletions occur in dystrophins central domain, generally considered to be a monotonous rod-shaped domain based on the knowledge of spectrin family proteins. However, the effects caused by these deletions, ranging from asymptomatic to severe BMD, argue against the central domain serving only as a featureless scaffold. We undertook structural studies combining small-angle X-ray scattering and molecular modeling in an effort to uncover the structure of the central domain, as dystrophin has been refractory to characterization. We show that this domain appears to be a tortuous and complex filament that is profoundly disorganized by the most severe BMD deletion (loss of exons 45–47). Despite the preservation of large parts of the binding site for neuronal nitric oxide synthase (nNOS) in this deletion, computational approaches failed to recreate the association of dystrophin with nNOS. This observation is in agreement with a strong decrease of nNOS immunolocalization in muscle biopsies, a parameter related to the severity of BMD phenotypes. The structural description of the whole dystrophin central domain we present here is a first necessary step to improve the design of microdystrophin constructs toward the goal of a successful gene therapy for DMD.

Docking de protéines en réalité virtuelle: Une approche hybride et multimodale

Protein docking studies 3d combination of proteins, in order to better understand their functions. French projet CoRSAIRe aims at increasing docking efficiency with multimodal VR interactions. On the basis of ergonomic analysis, we have designed an immersive application where visual, audio and haptic feedbacks communicate biological information.

Semantics for an Integrative and Immersive Pipeline Combining Visualization and Analysis of Molecular Data

Abstract The advances made in recent years in the field of structural biology significantly increased the throughput and complexity of data that scientists have to deal with. Combining and analyzing such heterogeneous amounts of data became a crucial time consumer in the daily tasks of scientists. However, only few efforts have been made to offer scientists an alternative to the standard compartmentalized tools they use to explore their data and that involve a regular back and forth between them. We propose here an integrated pipeline especially designed for immersive environments, promoting direct interactions on semantically linked 2D and 3D heterogeneous data, displayed in a common working space. The creation of a semantic definition describing the content and the context of a molecular scene leads to the creation of an intelligent system where data are (1) combined through pre-existing or inferred links present in our hierarchical definition of the concepts, (2) enriched with suitable and adaptive analyses proposed to the user with respect to the current task and (3) interactively presented in a unique working environment to be explored.