Enhanced sampling and applications in protein folding in explicit solvent

TL;DR

This paper introduces a single-copy tempering method utilizing a novel integral identity for efficient protein folding simulations in explicit solvent, achieving atomic accuracy within microseconds.

Contribution

The paper presents a new single-copy tempering approach with a runtime energy estimate guiding temperature-space random walks, validated on complex systems and applied to protein folding.

Findings

Successfully folded three small proteins to atomic accuracy

Validated method on Ising and Lennard-Jones models

Achieved folding within 0.5-1 microsecond

Abstract

We report a single-copy tempering method for simulating large complex systems. In a generalized ensemble, the method uses runtime estimate of the thermal average energy computed from a novel integral identity to guide a continuous temperature-space random walk. We first validated the method in a two-dimensional Ising model and a Lennard-Jones liquid system. It was then applied to folding of three small proteins, trpzip2, trp-cage, and villin headpiece in explicit solvent. Within 0.5~1 microsecond, all three systems were folded into atomic accuracy: the alpha carbon root mean square deviations of the best folded conformations from the native states were 0.2 A, 0.4 A, and 0.4 A, for trpzip2, trp-cage, and villin headpiece, respectively.