Illustration of the atomic structure of the capsid of HIV-1 (PDB ID: 3J3Q) using the VTX visualization software.
Illustration of the 3rd person navigation mode in UDock within the IL-6/IL-6R/gp130 complex (PDB ID: 1P9M). UDock is freely available at http://udock.fr
want to annotate biological networks, it could be interesting to have methods that can be applied in a high-throughput manner,” he continues. “Which proteins interact with each other in a cell?”
Udock software
Mapping the future of drug design Maps help us find our way around an area, assess the local topology and identify places of interest, and a similar level of detail on protein surfaces could be very beneficial in drug design and theoretical biology. We spoke to Professor Matthieu Montes about the work of the VIDOCK project in developing new representations of molecular objects. A physical map provides detailed information on the topology and geographical features of a region, helping visitors to find their way around and identify locations of interest. A comparable level of detail on the shape and form of protein surfaces would be invaluable in drug design and development, a topic central to the work of the VIDOCK project. “The idea is to work on the representation of molecular objects, proteins in particular. We want to represent the shape of proteins, and then to characterise the function by comparing the shapes,” explains Professor Matthieu Montes, the project’s Principal Investigator. The aim here is to characterise the topology of a molecule, which then opens up the possibility of identifying similarities between proteins, or molecular objects in general. “The idea is to characterise the shape of molecules, in order to identify potential partners,” continues Professor Montes. 12
2-D Conformal maps This work involves effectively transforming 3-dimensional representations of proteins into 2-dimensional maps, which will complement the information that is already available. A lot of attention in the project
comparison of protein shapes. “We focus on the 2-d description of the shape, although there are also 3-d descriptors that we use. We describe the shape of a protein as a combination of different surface features,” continues Professor Montes.
The idea is to work on the representation of molecular objects, proteins in particular. We want to represent the shape of proteins, and then to characterise the function by comparing the shapes. is focused in particular on local shape comparison, yet researchers currently lack a clear basis on which to classify proteins in this way. “There are classifications of proteins, but not shape-based classification of proteins,” explains Professor Montes. It is necessary to first establish a benchmark, which then provides a reference point for the subsequent
The Protein Data Bank (PDB) is an invaluable resource in this respect, providing detailed information on the shapes and structure of different proteins. From this type of information, Professor Montes and his colleagues can then derive different descriptors. “For example, in the project we are using a descriptor based on local convexity”
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he outlines. The information that has been gathered about the surface of a protein is projected onto a unique sphere, which acts as a point of comparison. “We have information about the coordinates on the surface, and we project each point of the surface onto the unique sphere,” says Professor Montes. “This sphere is then projected onto a plan, similar to the process of producing a cartographical map.” Researchers aim to develop a prototype conformal mapping tool which provides accurate, reliable information on the topology of a protein. This information will prove complementary to that provided by existing 3-D representations of protein surfaces. “The idea is to enable high-throughput comparison of molecular changes,” explains Professor Montes. This work holds clear relevance to drug design and development, potentially enabling researchers to identify molecules with therapeutic potential significantly quicker than is currently possible, while Professor Montes says it could also be applied in theoretical biology. “For example, if you
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A second aspect of the project’s work involves the development of a piece of software called Udock to simulate protein docking. One of the applications researchers are focusing on is using Udock for molecular dynamics simulations; with current methods, it’s necessary to prepare a simulation beforehand. “Before launching a simulation, you have to prepare the geometry of the initial configuration of your system. Each component of the simulation – such as the proteins and the membrane – needs to be prepared, then they are put together,” explains Professor Montes. The focus in the project is on developing a more accessible, easy to use system, that will enable researchers to accurately and conveniently simulate protein
docking. “With Udock we focused on ease of use, and simplifying the interface as far as possible,” says Professor Montes. This approach is very much in line with the needs of researchers. While experimental biologists and experimental chemists hold deep expertise in their own field, Professor Montes says they may not necessarily be software experts. “People from experimental sciences often need to generate illustrations of their systems, or to do certain calculations. Sometimes they cannot perform these experiments, as the tools available are not usable for non-experts,” he explains. Ensuring that the software is accessible and easy to use is a correspondingly high priority, while more experienced users will also benefit from a specialised interface and better designed tools. “We aim to simplify the interface, to enable users to focus on the specific task they have to perform. Everything in the interface is dedicated to the task that they are performing,” continues Professor Montes.
Illustration of UDock classic mode with the Barnase/Barstar complex (PDB ID: 1BRS). UDock is freely available at http://udock.fr
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VIDOCK 2D Conformal mapping of protein surfaces: applications to VIsualization and DOCKing software
Project Objectives
The goals of structural biology include developing a comprehensive understanding of the molecular shapes and forms embraced by biological macromolecules and extending this knowledge to understand how different molecular architectures are used to perform the chemical reactions that are central to life. Since the first resolution of protein structures by X-ray crystallography and NMR, structural biology seeks to provide this picture of biological phenomena at the molecular and atomic level by analyzing 3D structures. In the ViDOCK project, we develop new representations of protein surfaces that will open avenues for the development of 1. highthroughput protein shape-comparison methods and 2. Interactive visualization and simulation methods such as molecular docking.
Project Funding
This work is funded by the European Research Council Executive Agency under the research grant number #640283
Project Collaborators
• ILJ Team, Laboratoire CEDRIC, EA4629, CNAM • M2Disco Team, LIRIS, UMR 5205 CNRS/ INSA Lyon/Université de Lyon • XLIM, UMR 7252 CNRS, Université de Limoges • LCT, Sorbonne Université
Contact Details
Project Coordinator, Professor Matthieu Montes Laboratoire GBCM, EA7528 Conservatoire National des Arts et Métiers 2 rue Conté, 75003 Paris, France T: +33140272809 E: matthieu.montes@cnam.fr W: http://vidock.eu
Professor Matthieu Montes
Matthieu Montes is Professor of bioinformatics and head of the molecular modelling and drug design team at Conservatoire National des Arts et Métiers in Paris. His research interests include molecular modelling, drug discovery and design, interactive simulation methods and computational geometry.
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Researchers are also working on interfacing Udock with simulation software, which could help in the representation of bigger systems. This is currently a major bottleneck for researchers working on molecular dynamics simulations, so the aim again is to develop a more useable way of generating the scenes for these larger systems. “The goal is to overcome the limits of the currently available visualisation software,” explains Professor Montes. The nature of this work crosses disciplinary boundaries, and close collaborations have been established with researchers in complementary disciplines to explore further possibilities. “We have established a collaboration with people working in computer graphics, to generate a new graphics engine, which will allow us to visualise very big systems,” says Professor Montes.
Sonification A further aspect of the project’s work involves the representation of data through sound, a technique called sonification. The idea itself is very simple, says Professor Montes. “You have a sound feedback that gives you information about a particular problem. For example, with cars we have sound feedback that tells you how close you are to an object when you are parking,” he explains. The shape of a protein could potentially be represented in a similar way with sound, a topic researchers are investigating in the project, alongside looking at how to distinguish between different shapes using sound. “We could modulate a rhythm for example. The idea is to make it noticeable and informative,” explains Professor Montes. The project as a whole is very much interdisciplinary in scope, and collaboration and knowledge-sharing has been a central feature. This has helped to lay the foundations for further research, says Professor Montes. “Links
have been established between structural biologists, drug designers, and people working in computer graphics. We’ve also been working with computer scientists and applying ideas from robotics and computer vision,” he outlines. One major outcome from the project has been to bring researchers in the robotics and applied mathematics fields together with structural biologists, work which has already yielded exciting results. “We published the first version of the global shape comparison prototype at a recent computer science conference,” continues Professor Montes. This work forms part of a long history of pioneering French research and technical innovation, the story of which is highlighted at the Musée des arts et métiers at CNAM, where Professor Montes is based. His own work is featured at the museum, which he hopes will help heighten awareness of his group’s research. “There are displays of new technologies from earlier periods of history, such as early computers and planes. Udock will be displayed alongside other prototypes and scientific tools,” says Professor Montes. It will also be displayed in an exhibition of cartographic tools at the museum. “This includes both celestial and terrestrial globes. Alongside these globes, there will be a dedicated version of Udock, that allows interactive and real-time projection of a protein surface” explains Professor Montes. The idea here is to draw a parallel between celestial objects and microscopic objects, such as proteins, as the techniques involved in projecting them are the same. By making scientific research more accessible to the wider public, Professor Montes hopes the feature at the museum will help stimulate greater interest in science. “There will be a temporary screen where people can select a protein and project it in real-time. They will then be able to navigate on the map”, he outlines.
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