Revision of the GROMOS 56A6CARBO force field: Improving the description of ring‐conformational equilibria in hexopyranose‐based carbohydrates chains

This article describes a revised version 56A6CARBO_R of the GROMOS 56A6CARBO force field for hexopyranose‐based carbohydrates. The simulated properties of unfunctionalized hexopyranoses are unaltered with respect to 56A6CARBO. In the context of both O1‐alkylated hexopyranoses and oligosaccharides, the revision stabilizes the regular 4C1 chair for α‐anomers, with the opposite effect for β‐anomers. As a result, spurious ring inversions observed in α(1→4)‐linked chains when using the original 56A6CARBO force field are alleviated. The 4C1 chair is now the most stable conformation for all d‐hexopyranose residues, irrespective of the linkage type and anomery, and of the position of the residue along the chain. The methylation of a d‐hexopyranose leads to a systematic shift in the ring‐inversion free energy (4C1 to 1C4) by 7–8 kJ mol−1, positive for the α‐anomers and negative for the β‐anomers, which is qualitatively compatible with the expected enhancement of the anomeric effect upon methylation at O1. The ring‐inversion free energies for residues within chains are typically smaller in magnitude compared to those of the monomers, and correlate rather poorly with the latter. This suggests that the crowding of ring substituents upon chain formation alters the ring flexibility in a nonsystematic fashion. In general, the description of carbohydrate chains afforded by 56A6CARBO_R suggests a significant extent of ring flexibility, i.e., small but often non‐negligible equilibrium populations of inverted chairs, and challenges the “textbook” picture of conformationally locked carbohydrate rings. © 2015 Wiley Periodicals, Inc.