Fast sampling of A-to-B protein global conformational transitions: from Galileo Galilei to Monte Carlo anisotropic network modeling.

Local and global conformational transitions underlie protein function. Local changes include induced-fit effects such as the reorientation of residues. Global motions may involve interdomain motion, allosteric switches, and the dynamics of secondary structure elements several nanometers distant from each other (1). Global conformational changes are activated processes, thus particularly challenging for traditional atomistic simulation, because sampling can be prohibitively slow or activated by rare events. The easiest simulation scenario arises when at least knowledge of two states of interest, A and B, is available; these states can be assumed the most relevant and the problem is reduced to two key questions: what are the most convenient pathways connecting A to B, and vice versa? Does one unique, most favorable pathway exist?