Revision of the GROMOS 56A6_CARBO force field: Improving the description of ring‐conformational equilibria in hexopyranose‐based carbohydrates chains

Abstract

This article describes a revised version 56A6(CARBO_R) of the GROMOS 56A6(CARBO) 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 (4) C1 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 56A6(CARBO) force field are alleviated. The (4) C1 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 ((4) C1 to (1) C4 ) 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 56A6(CARBO_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.

Solvent‐Modulated Influence of Intramolecular Hydrogen‐Bonding on the Conformational Properties of the Hydroxymethyl Group in Glucose and Galactose: A Molecular Dynamics Simulation Study

“…Note, however, that if O(1)‐methylation has essentially no influence on the relative populations of the rotamers for Glc, it leads to changes of about 15% in the gt and tg populations for Gal. This effect was also observed within the 56A6 CARBO_R force field (see Table 7 therein).…”

“…Such conformations, which present only marginal populations experimentally for unfunctionalized hexopyranoses (with the exception of idose), have been seen to occur in previous simulations owing to force‐field inaccuracies. The 53A6 force field is a priori likely to be more prone to ring distortions considering that, unlike the 56A6 CARBO force field (see also Ref . for the revised version 56A6 CARBO_R ), its parameterization did not involve the consideration of ring‐conformational free energies …”

“…For Glc and Gal, this is again consistent with the results of other studies using this force field (see Supplementary Material , Table S.1 ), e.g . 35:60:5 and 6:52:42 in Ref . ( β ‐anomer, free lactol group).…”

“…. The first two compounds differ in the orientation of the hydroxyl group at C(4), equatorial for Glc and axial for Gal in the 4 C 1 chair conformation, the most stable one in aqueous solution for these compounds . The last compound lacks the hydroxyl group.…”

Acyclic forms of aldohexoses and ketohexoses in aqueous and DMSO solutions: conformational features studied using molecular dynamics simulations

“…22 The parameters for the studied compounds were generated using Automated Topology Builder (ATB) 2.2. 23 Note that the considered hexoses have the acyclic form, therefore the usual, carbohydrate-dedicated force fields [7][8][9][10][11][12] are not applicable. Fig.…”