Conformational free energies of methyl-$\alpha$-L-iduronic and methyl-$\beta$-D-glucuronic acids in water

TL;DR

This paper introduces a simulation protocol combining non-equilibrium umbrella sampling and Hamiltonian replica exchange to efficiently compute free energies of methyl glycosides in water, reducing computational costs.

Contribution

The authors develop a novel simulation approach that improves sampling efficiency and accuracy for free energy calculations of flexible solutes in explicit solvent.

Findings

Efficient sampling of puckering landscapes achieved

Significant reduction in computational resources compared to parallel tempering

Accurate free energy profiles obtained for methyl glycosides in water

Abstract

We present a simulation protocol that allows for efficient sampling of the degrees of freedom of a solute in explicit solvent. The protocol involves using a non-equilibrium umbrella sampling method, in this case the recently developed adaptively biased molecular dynamics method, to compute an approximate free energy for the slow modes of the solute in explicit solvent. This approximate free energy is then used to set up a Hamiltonian replica exchange scheme that samples both from biased and unbiased distributions. The final accurate free energy is recovered via the WHAM technique applied to all the replicas, and equilibrium properties of the solute are computed from the unbiased trajectory. We illustrate the approach by applying it to the study of the puckering landscapes of the methyl glycosides of $\alpha$-L-iduronic acid and its C5 epimer $\beta$-D-glucuronic acid in water. Big savings in computational resources are gained in comparison to the standard parallel tempering method.