Resolution exchange with tunneling for enhanced sampling of protein landscapes.

Abstract

Simulations of protein folding and protein association happen on timescales that are orders of magnitude larger than what can typically be covered in all-atom molecular dynamics simulations. Use of low-resolution models alleviates this problem but may reduce the accuracy of the simulations. We introduce a replica-exchange-based multiscale sampling technique that combines the faster sampling in coarse-grained simulations with the potentially higher accuracy of all-atom simulations. After testing the efficiency of our Resolution Exchange with Tunneling (ResET) in simulations of the Trp-cage protein, an often used model to evaluate sampling techniques in protein simulations, we use our approach to compare the landscape of wild-type and A2T mutant Aβ_{1-42} peptides. Our results suggest a mechanism by that the mutation of a small hydrophobic alanine (A) into a bulky polar threonine (T) may interfere with the self-assembly of Aβ fibrils.