Structural BioInformatic  - Michael NILGES

Activities of the Unit

We use mainly computational methods to study the structure and function of biological macromolecules. (1) We develop methods to model structures of biological molecules and their complexes from experimental data (mostly NMR; T. Malliavin,  M. Nilges). We are working on applications of our recently developed Bayesian methods to the determination of large assemblies from heterogeneous data. (2) We use and develop molecular dynamics and computational docking methods to enhance our knowledge of the protein conformational landscape, and to analyse the relationship between internal dynamics/ conformational changes and protein-ligand interactions (A. Blondel, T. Malliavin, M. Nilges). (3) P.L. Chau studies the mode of action of general anaesthetics with experimental (neutron scattering) and computer simulation methods, to characterize the interactions of drugs with membranes and with the putative membrane protein target (P.L. Chau). (4) E. Yeramian employs powerful biophysics concepts to develop and enhance bioinformatics methods (applications include large-scale models of nucleic acids and probabilistic sequence alignment).

View of halothane docked to its putative binding site of   
a GABA_A receptor model  

  The EF toxin of Anthrax is activated in the victim’s cells by a conformation transition. The transition was modeled (green, lime, yellow, orange and red conformations) to find a mean to block the toxin in an inactive conformation. A cavity (white volume in the models) which shrinks early in the transition was identified. Molecules which could fill that  cavity were searched in chemical libraries by computation. Of 28 thus selected molecules, 6 could block the toxin activity, illustrating that comprehensive modeling of structural transitions could create a disruptive widening of the opportunities to identify drug candidates.                                     

Most significant publications :

Rieping W, Habeck M, Nilges M (2005). Inferential structure determination. Science 309, 303-306.

Grünberg R, Nilges M, Leckner J (2006) Flexibility and Conformational Entropy in Protein-Protein Binding Structure 14, 683–693.

Chau P-L, Hoang PNM, Picaud S, Jedlovszky P (2007). A possible mechanism for pressure reversal phenomenon of general anaesthetics from molecular simulations, Chemical Physics Letters, 438, 294-297.

Yeramian E, Debonneuil E (2007) Probabilistic sequence alignments: realistic models with efficient algorithms. Phys Rev Lett. 98: 078101-078104.

Laine E, Blondel A, Malliavin TE (2009) Dynamics and energetics: a consensus analysis of the impact of calcium on EF-CaM protein complex., Biophysical J. 96, 1249-1263.