Structural Biology

Biography

Biography: Chantal Prévost

Abstract

Statement of the Problem: Many proteins present highly flexible or disordered fragments, either terminal tails or surface loops. Although they often form instable and transient interactions, these fragments play essential roles in regulating macromolecular association or controlling the architecture of supramolecular complexes. The role of their conformational variability in complex formation is poorly understood and requires the development of specific approaches.

Methodology & Theoretical Orientation: We have studied the effect of protein segment conformational variability in protein-protein complex formation as well as peptide docking using theoretical docking approaches. Notably, we have developed a flexible docking method that accounts for the presence of flexible loops, together with analysis protocols that capture the entropic effects associated to structural variability in flexible docking results. 

Findings:  Whether the flexible segment is a loop or a peptide, we have found that a given mode of association can be stabilized by different  conformations of the segment.  Alternatively, different loop conformations can stabilize different modes of protein-protein association.

Conclusion & Significance: Tolerance of a binding site to conformational variability, as observed in protein-peptide docking but also in the association of proteins with flexible loops or segments, can play a role in adding a conformational entropy component to the energy of association, thus favoring the initial binding of the flexible fragment to its binding site. For proteins that associate using different binding geometries, either with different partners or along a functional pathway, loop flexibility can also be used to regulate the choice of  the binding geometry. 

References:

1. Sacquin-Mora S, Prévost C (2015) Docking peptides on proteins: How to open a lock, in the dark, with a flexible key. Structure, 23:1373-1374.
2. Laurin Y, Savarin P, Robert C, Takahashi M, Eyer J, Prévost C, Sacquin-Mora S (2015) Investigating the binding modes of the glioma targeting NFL-TBS.40-63 peptide on tubulin via docking and molecular dynamics simulations. Biochemistry 54:3660-3669.
3. Bastard K, Thureau A, Lavery R and Prévost C (2003) Docking macromolecules with flexible segments. Journal of Computational Chemistry, 24:1910-1920.
4. Bastard K, Prévost C and Zacharias M (2006) Accounting for loop flexibility during protein-protein docking. Proteins: Structure, Function and BioInformatics, 62:956-969
5. Boyer B,  Ezelin J, Poulain P, Saladin A, Zacharias M,  Robert CH, Prévost C (2015). An integrative approach to the study of filamentous oligomeric assemblies, with application to RecA. PLoS ONE 10(3):e0116414.