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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