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Section: New Results

Structural Systems Biology

Participants : Marie-Dominique Devignes, Bernard Maigret, David Ritchie, Malika Smaïl-Tabbone.

Keywords:

bioinformatics, chemistry, docking, knowledge discovery, screening, systems biology

Structural systems biology aims to describe and analyze the many components and interactions within living cells in terms of their three-dimensional (3D) molecular structures. We are currently developing advanced computing techniques for molecular shape representation, protein-protein docking, protein-ligand docking, high-throughput virtual drug screening, and knowledge discovery in databases dedicated to protein-protein interactions.

The Hex Protein Docking Program

Our Hex protein docking software is being more widely used than ever before. The unique polar Fourier correlation approach used in Hex [129] allows the expensive FFT part of its calculations to be greatly accelerated on modern graphics processors (GPUs) [130] . Hex is freely available for download for academic users at http://hex.loria.fr . A public GPU-powered server has also been created (http://hexserver.loria.fr ) [123] . In the last four years, the server has performed some 63,700 docking runs, and the program has had some 37,000 downloads. The latest version of the program has been used successfully to dock symmetric dimers (unpublished results) in the international “CAPRI” docking experiment [115] . A manuscript on performing polar Fourier docking using symmetry constraints is in preparation with the Nano-D team at Inria Grenoble.

KBDOCK: Protein Docking Using Knowledge-Based Approaches

In order to explore the possibilities of using structural knowledge of protein-protein interactions, Anisah Ghoorah recently developed the KBDOCK system as part of her doctoral thesis project [116] . KBDOCK is available at http://kbdock.loria.fr . KBDOCK combines coordinate data from the Protein Data Bank [106] with the Pfam protein domain family classification [111] in order to describe and analyze all known protein-protein interactions for which the 3D structures are available. We have demonstrated the utility of KBDOCK [114] for template-based docking using 73 complexes from the Protein Docking Benchmark [117] . We recently presented results obtained using KBDOCK at the CAPRI conference on protein docking in Utrecht [115] . In late 2013, we updated KBDOCK with the latest data from Pfam and the Protein Data Bank. In 2014, an article describing the new version of KBDOCK was published in the special Database Issue of Nucleic Acids Research [10] . Since the KBDOCK web site (http://kbdock.loria.fr ) was created in 2011, it has had over 12,000 distinct visitors.

Kpax: A New Algorithm for Multiple Flexible Protein Structure Alignments

We recently developed a new protein structure alignment approach called Kpax [128] . The approach exploits the fact that each amino acid residue has a carbon atom with a highly predictable tetrahedral geometry. This allows the local environment of each residue to be transformed into a canonical orientation, thus allowing easy comparison between the canonical orientations of residues within pairs of proteins using a novel scoring function based on Gaussian overlaps. The overall approach is two or three orders of magnitude faster than most contemporary protein structure alignment algorithms, while still being almost as accurate as the state-of-the-art TM-Align approach [134] . Kpax is now used heavily by the KBDOCK web server [10] to find structural templates for docking which might be beyond the reach of sequence-based homology modeling approaches. The Kpax program is also available for download at http://kpax.loria.fr/ .

In 2014, the Kpax algorithm has been extended to allow flexible alignment and superposition of protein backbones and to perform multiple structure alignments, in analogy with multiple protein sequence alignments. Our early results show that incorporating backbone flexibility leads to much higher quality multiple alignments than can be achieved with existing algorithms.

Polypharmacology: Developing New Uses for Old Drugs

In 2010, Violeta Pérez-Nueno joined the Orpailleur team thanks to a Marie Curie Intra-European Fellowship (IEF) award to develop new virtual screening algorithms (DOVSA). The aim of this project was to advance the state of the art in computational virtual drug screening by developing a novel consensus shape clustering approach based on spherical harmonic (SH) shape representations [126] .

In 2012, Violeta joined Harmonic Pharma, a LORIA spin-out company for drug re-purposing, and we have since continued our collaborations to develop new algorithms for drug discovery and drug re-purposing. The observation that many existing drugs may be used to treat more than one disease is often referred to as “polypharmacology.” Our latest work on predicting polypharmacology uses a Gaussian clustering approach to identify groups molecules with similar three-dimensional shapes. This work was published in the Journal of Chemical Information and Modeling [44] . An illustration from this article was used to provide the cover page for the March 2014 issue of the journal (http://pubs.acs.org/toc/jcisd8/54/3 ).