Dynamic Heterogeneity and the Role of Non-Native Contacts in the Protein Folding/Unfolding Transitions

Abstract

The understanding of protein dynamics have greatly deepened over the last few decades. Protein folding has been an ideal example to study how the conformational transitions of protein occurs in a highly synchronous manner. In addition, recent advances in computational and experimental tools are allowing us to explore how the dynamics occur at the atomic level in further detail. Yet, due to the high-dimensional nature of protein molecules, obtaining a simple and sufficient picture to understand the dynamics is still a challenging task.Here, we study a small alpha-helical protein, villin headpiece (HP35), from a theoretical prespective to reveal the mechanism of folding/unfolding transition and the dynamics at atomic level. We apply the dynamics component analysis method (TM and SS, J. Chem. Phys. 142, 135101 (2015)), a method designed to determine the coordinates based on the slowness of the modes, to the ∼300 µs all-atom molecular dynamics trajectories of HP35 and its mutant, obtained by D. E. Shaw Research (S. Piana et al., PNAS 109, 17845 (2012)).We find that the folding/unfolding transition occurs in a highly heterogeneous manner, e.g. transition path times within a trajectory differ by more than two orders of magnitudes. This strongly indicates that the transition occurs via multiple pathways, which is in contrast to a one-dimensional free energy landscape picture. Indeed, we find that at least two folding/unfolding transition pathways exist. Furthermore, multiple locally trapped structures are found along the transition pathways. We discuss how non-native contacts seem to play a role in such “kinetic traps”. Overall, the current result reveal the hidden complexity in the protein folding/unfolding transition dynamics, even for a well-studied small proteins such as HP35.