Dependence of Sidechain Rotamer Preference on Backbone Conformation: Relative Free Energy Calculations for Valine and Leucine

TL;DR

This study uses free energy calculations to explore how backbone conformation influences sidechain rotamer preferences in valine and leucine, aligning with existing rotamer libraries and suggesting applications in peptide structure prediction.

Contribution

It introduces a method combining umbrella sampling and WHAM to directly compute backbone-dependent sidechain rotamer preferences from molecular dynamics simulations.

Findings

Preferences align with established rotamer libraries

Method accurately captures backbone-dependent rotamer distributions

Potential for extending to peptide structure refinement

Abstract

Three dimensional relative free energy calculations are used to directly calculate the dependence of the preferred sidechain rotamers for valine and leucine on the conformation of the backbone. Specifically, umbrella restrained molecular dynamics calculations are used to sample all of Ramachandran space for chi values surrounding the common rotameric states of leucine and valine. Relative free enegy slices were calculated from the biased trajectories using the weighted histogram analysis method (WHAM). The slices were connected together by another set of slices perpendicular to Ramachandran space to determine the favored rotamer for a given backbone conformation. The calculated preferences are quite similar to those seen in the backbone-dependent rotamer library of Dunbrack and Karplus, despite the fact that the current calculations neglect the effects of neighboring residues. It appears likely that these calculations could be extended to calculate the optimal sidechain conformation for a peptide with known backbone conformation in the context of structure refinement and prediction