Molecular simulations of protein binding events

Liliane Chong,
University of Pittsburg, U.S.A.
Mardi, 23 octobre 2012, 11 h 00, Bibliothèque du LCT, tour 12-13, 4e étage

The motions of proteins are important for a variety of biological processes, including protein binding, enzyme catalysis, and signal transduction. These motions occur on a wide range of timescales; for example, side chains move on a picosecond timescale, the relative motions of protein domains occur on a nanosecond timescale, and allosteric transitions occur on the microsecond timescale. The characterization of these motions is of great interest since the identification of features such as alternate conformations or transient binding pockets could potentially aid the development of new classes of pharmaceuticals.

In principle, molecular dynamics (MD) simulations can provide the time resolution and atomic detail necessary for monitoring the step-by-step progression of protein motions. In practice, however, it has not been possible to simulate biologically relevant timescales using typical computing resources. There remains therefore a need for strategies that enable the simulation of these longer timescale events. One possibility is to take advantage the fact that some processes of interest, e.g. protein folding and binding, appear to be slow not because the transitions themselves are slow, but rather because they are infrequent events. In this talk, I will show how exploiting this aspect has allowed significant progress to be made towards simulations of protein binding events, including detailed views of how nature might correct for "mistakes" in binding orientation.