Rapid calculation of side chain packing and free energy with applications to protein molecular dynamics

TL;DR

This paper introduces a fast, self-consistent approximation method for calculating side chain free energies in proteins, enabling rapid molecular dynamics simulations and accurate predictions of side chain conformations.

Contribution

The authors develop a novel, efficient approach to compute side chain free energies on the fly, significantly speeding up protein simulations and improving rotamer prediction accuracy.

Findings

Achieves millisecond-level computation of side chain free energies.

Accurately predicts $\ ext{\chi}_1$ rotamer states.

Enables de novo folding of some proteins with high accuracy.

Abstract

To address the large gap between time scales that can be easily reached by molecular simulations and those required to understand protein dynamics, we propose a rapid self-consistent approximation of the side chain free energy at every integration step. In analogy with the adiabatic Born-Oppenheimer approximation for electronic structure, the protein backbone dynamics are simulated as preceding according to the dictates of the free energy of an instantaneously-equilibrated side chain potential. The side chain free energy is computed on the fly, allowing the protein backbone dynamics to traverse a greatly smoothed energetic landscape. This results in extremely rapid equilibration and sampling of the Boltzmann distribution. Because our method employs a reduced model involving single-bead side chains, we also provide a novel, maximum-likelihood method to parameterize the side chain model using input data from high resolution protein crystal structures. We demonstrate state-of-the-art accuracy for predicting $\chi_1$ rotamer states while consuming only milliseconds of CPU time. We also show that the resulting free energies of side chains is sufficiently accurate for de novo folding of some proteins.