Resolution exchange with tunneling for enhanced sampling of protein landscapes

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 A beta(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 A beta fibrils.

Automated summary

Simulations of protein folding and protein association typically take much longer timescales than can be covered in all-atom molecular dynamics simulations. To address this challenge, researchers have introduced 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. By testing the efficiency of this technique in simulations of the Trp-cage protein and comparing the landscapes of wild-type and A2T mutant A beta(1-42) peptides, the researchers found a mechanism by which a small hydrophobic alanine (A) mutation to a bulky polar threonine (T) may interfere with the self-assembly of A beta fibrils.