The aim of our research is to complement structural studies (X-rays, NMR, Electron microscopy) with in silico studies, to:

• better determine and predict three-dimensional structures;

• better understand molecular recognition and molecular interactions.

Our research topics include medically relevant molecular processes (infectious diseases, cancer, and the action of general anesthetics). Collaboration with experimental groups on campus, and our own experimental projects, are of fundamental importance for the group.

New strategies for the structural analysis of NMR data developed in the group make experimental structure determination more reliable, and allow obtaining an unbiased estimate of quality of an NMR structure. Recent efforts are in integrated structural biology approaches, combining heterogeneous and sparse data with structural knowledge and comparative modeling to obtain high-resolution models of larger complexes. Other developments include new probabilistic methods for sequence alignment, RNA structure prediction, and gene prediction by physics based genome analysis.

Studies on the dynamics of protein-protein interactions by docking and molecular dynamics calculations have provided new insights into the interplay between protein flexibility and molecular recognition. The prediction of conformational changes during the binding of a protein and a small ligand, remains a challenging aim. We have successfully used such predictions in the identification of novel therapeutic agents. In several collaborations with experimental groups we use ligand docking and virtual screening. Targets include proteins from P. falciparum, T. brucei, T. cruzi, M. tuberculosis and B. anthracis. We have identified inhibitors for proteins from P. falciparum, M. tuberculosis, T. cruzi and B. anthracis that were validated experimentally.

The work on general anesthetics includes two axes: the study of the GABA_A receptor using structure prediction and computer simulations on this system to elucidate its mechanism of action, and the study of the interaction of general anesthetics and membranes. Our previous work has suggested a mechanism for the pressure-induced reversal of general anesthetic action, and we are now verifying this mechanism using neutron scattering experiments and free-energy change calculations.

Keywords: Structural Bioinformatics, Molecular Dynamics, Genome Analysis, Gene Prediction, Structure Prediction, Protein-Protein Interactions, NMR data analysis

Chau, PL; Hoang, PNM; Picaud, S; Jedlovszky, P. 2007. A possible mechanism for pressure reversal of general anaesthetics from molecular simulations. CHEM PHYS LETT 438 (4-6): 294-297.

Yeramian, E; Debonneuil, E. 2007. Probabilistic sequence alignments: Realistic models with efficient algorithms. PHYS REV LETT 98 (7): art. no.-078101.

Nilges, M; Bernard, A; Bardiaux, B; Malliavin, T; Habeck, M; Rieping, W. 2008. Accurate NMR structures through minimisation of an extended hybrid energy. STRUCTURE 16(9):1305-1312.

Laine, E; Goncalves, C; Karst, JC; Lesnard, A; Rault, S; Tang, WJ; Malliavin, TE; Ladant, D; Blondel, A. 2010. Use of allostery to identify inhibitors of calmodulin-induced activation of Bacillus anthracis edema factor. Proc. Natl. Acad. Sci USA 107:11277-11282.

Campos M, Nilges M, Cisneros D, Francetic O. 2010. Molecular model of the type II secretion pilus from sparse biochemically derived distances. Proc. Natl. Acad. Sci USA 107:13081-13086.