Further refinement and validation of the Drude polarizable force field for carboxylate and n-acetyl amine hexopyranose derivatives

Abstract

In this study, we present an improved parameter set for the Drude polarizable force field optimized to accurately capture the ring dynamics of four types of carboxylate- and N-acetyl amine-substituted aldohexoses and their anomers: α/β-d-glucuronate (AGLCA/BGLCA), α/β-l-iduronate (AIDOA/BIDOA), N-acetyl-α/β-d-galactosamine (AGALNA/BGALNA), and N-acetyl-α/β-d-glucosamine (AGLCNA/BGLCNA). This refinement builds on recent advances in the Drude polarizable force field, which previously demonstrated improved ring dynamics for unsubstituted monosaccharides. The new parameter set addresses discrepancies between calculated and experimental NMR 3J coupling constants, particularly in the description of ring and exocyclic torsional dynamics for hexopyranose derivatives. To evaluate its performance, we simulate multimicrosecond trajectories and compare the refined Drude parameter set with the CHARMM36 additive and GLYCAM06 additive force fields. Additionally, we used extended system adaptive biasing force (eABF) simulations to assess the conformational sampling efficiency of the different force fields. Our results show that polarization significantly enhances the sampling of ring conformations, resulting in better agreement with the ring based experimental NMR 3J coupling constants. Overall, the refined Drude polarizable force field, alongside the full set of Drude parameters, offers an improved tool for studying the conformational dynamics of carbohydrates and their conjugates in biomolecular systems.