Puckering Free Energy of Pyranoses Using a Combined Metadynamics-Umbrella Sampling Approach

TL;DR

This study uses combined metadynamics and umbrella sampling to analyze pyranose puckering free energies, revealing force field limitations and proposing parameter modifications for better accuracy.

Contribution

It introduces a combined simulation approach and suggests modifications to the gromos 45a4 force field to improve puckering free energy predictions.

Findings

Force field fails to reproduce correct free energy differences.

Inverted chair conformers are overpopulated in some sugars.

Parameter modifications improve agreement with experimental data.

Abstract

We present the results of a combined metadynamics-umbrella sampling investigation of the puckered conformers of pyranoses described using the gromos 45a4 force field. The free energy landscape of Cremer-Pople puckering coordinates has been calculated for the whole series of alpha and beta aldohexoses. We show that the 45a4 force field parameters fail in reproducing proper free energy differences between chair conformers for many of the inspected monosaccharides. In the extreme cases of galactose, mannose and allose, the experimentally non-detectable inverted chair conformers become even substantially populated. The opposite behavior is observed in the case of idose, which is the only experimentally known aldohexose that shows equilibrium between chair and inverted chair. We suggest a modification to the gromos 45a4 parameter set, which improves considerably the accordance of simulation results with theoretical and experimental estimates of puckering free energies.