Understanding the Impacts of Conformational Dynamics on the Regulation of Protein-Protein Association by a Multiscale Simulation Method

Complexes formed among diverse proteins carry out versatile functions in nearly all physiological processes. Association rates which measure how fast proteins form various complexes are of fundamental importance to characterize their functions. The association rates are not only determined by the energetic features at binding interfaces of a protein complex but also influenced by the intrinsic conformational dynamics of each protein in the complex. Unfortunately, how this conformational effect regulates protein association has never been calibrated on a systematic level. To tackle this problem, we developed a multiscale strategy to incorporate the information on protein conformational variations from Langevin dynamic simulations into a kinetic Monte Carlo algorithm of protein-protein association. By systematically testing this approach against a large-scale benchmark set, we found the association of a protein complex with a relatively rigid structure tends to be reduced by its conformational fluctuations. With specific examples, we further show that higher degrees of structural flexibility in various protein complexes can facilitate the searching and formation of intermolecular interactions and thereby accelerate their associations. In general, the integration of conformational dynamics can improve the correlation between experimentally measured association rates and computationally derived association probabilities. Finally, we analyzed the statistical distributions of different secondary structural types on protein-protein binding interfaces and their preference to the change of association rates. Our study, to the best of our knowledge, is the first computational method that systematically estimates the impacts of protein conformational dynamics on protein-protein association. It throws lights on the molecular mechanisms of how protein-protein recognition is kinetically modulated.