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 Aß_{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 Aß fibrils.

Bifurcated Hydrogen Bonds and the Fold Switching of Lymphotactin.

Lymphotactin (Ltn) exists under physiological conditions in an equilibrium between two interconverting structures with distinct biological functions. Using replica-exchange-with-tunneling, we study the conversion between the 2-folds. Unlike previously proposed, we find that the fold switching does not require unfolding of lymphotactin but proceeds through a series of intermediates that remain partially structured. This process relies on two bifurcated hydrogen bonds that connect the ß2 and ß3 strands and ease the transition between the hydrogen bond pattern by which the central three-stranded ß-sheet in the two forms differs.