Sampling of Protein Folding Transitions: Multicanonical Versus Replica Exchange Molecular Dynamics.

We compare the efficiency of multicanonical and replica exchange molecular dynamics for the sampling of folding/unfolding events in simulations of proteins with end-to-end β-sheet. In Go-model simulations of the 75-residue MNK6, we observe improvement factors of 30 in the number of folding/unfolding events of multicanonical molecular dynamics over replica exchange molecular dynamics. As an application, we use this enhanced sampling to study the folding landscape of the 36-residue DS119 with an all-atom physical force field and implicit solvent. Here, we find that the rate-limiting step is the formation of the central helix that then provides a scaffold for the parallel β-sheet formed by the two chain ends.