J N C, Guvench O, MacKerell AD, Yamaguchi T, Mallajosyula SS
Journal of chemical theory and computation •
We present a revised version of the Drude polarizable carbohydrate force field (FF), focusing on refining the ring and exocyclic torsional parameters for hexopyranose monosaccharides. This refinement addresses the previously observed discrepancies between calculated and experimental NMR coupling values, particularly in describing ring dynamics and exocyclic rotamer populations within major hexose monosaccharides and their anomers. Specifically, α-MAN, β-MAN, α-GLC, β-GLC, α-GAL, β-GAL, α-ALT, β-ALT, α-IDO, and β-IDO were targeted for optimization. The optimization process involved potential energy scans (PES) of the ring and exocyclic dihedral angles computed using quantum mechanical (QM) methods. The target data for the reoptimization included PES of the inner ring dihedrals (C1-C2-C3-C4, C2-C3-C4-C5, C5-O5-C1-C2, C4-C5-O5-C1, O5-C1-C2-C3, C3-C4-C5-O5) and the exocyclic torsions, other than the pseudo ring dihedrals (O1-C1-O5-C5, O2-C2-C1-O5, and O4-C4-C5-O5) and hydroxyl torsions used in the previous parametrization efforts. These parameters, in conjunction with previously developed Drude parameters for hexopyranose monosaccharides, were validated against experimental observations, including NMR data and conformational energetics, in aqueous environments. The resulting polarizable model is shown to be in good agreement with a range of QM data, experimental NMR data, and conformational energetics of monosaccharides in aqueous solutions. This offers a significant improvement of the Drude carbohydrate force field, wherein the refinement enhances the accuracy of accessing the conformational dynamics of carbohydrates in biomolecular simulations.
Analysis of crystal structures of hexose monosaccharides α-d-mannose (α-MAN), β-d-mannose (β-MAN), α-d-glucose (α-GLC), β-d-glucose (β-GLC), α-d-galactose (α-GAL), β-d-galactose (β-GAL), α-d-altrose (α-ALT), β-d-altrose (β-ALT), α-d-idose (α-IDO), and β-d-idose (β-IDO) reveals that the monosaccharide ring adopts multiple ring conformations. These ring conformations can be broadly classified as chair, half-chair, envelope, boat, and skew-boat conformations. The ability of the monosaccharide ring to adopt multiple conformations has been closely tied with their bioactivity. However, it has been difficult to capture the dynamic information of these conformations from experimental studies. Even from simulations, capturing these different conformations is challenging because of the energy barriers involved in the transitions between the stable C and C chair forms. In this study, we analyze the influence of the polarizable force field on the ring dynamics of five major types of unsubstituted aldohexoses─glucose, mannose, galactose, altrose, and idose─and their anomers. We simulate microsecond trajectories to capture the influence of the CHARMM36 additive and polarizable carbohydrate force fields on the ring dynamics. The microsecond trajectories allow us to comment on the issues associated with equilibrium molecular dynamics simulations. Further, we use the extended system adaptive biasing force (eABF) method to compare the conformational sampling efficiencies of the additive and polarizable force fields. Our studies reveal that inclusion of polarization enhances the sampling of ring conformations and lowers the energy barriers between the C and C conformations. Overall, the CHARMM36 additive force field is observed to be rigid and favor the C conformations. Although the inclusion of polarizability results in enhancing ring flexibility, we observe sampling that does not agree with experimental results, warranting a revision of the polarizable Drude parameters.