CHARMM Additive All-Atom Force Field for Glycosidic Linkages in Carbohydrates Involving Furanoses

Abstract

Presented is an extension of the CHARMM additive carbohydrate all-atom force field to enable modeling of polysaccharides containing furanose sugars. The new force field parameters encompass 1 ↔ 2, 1 → 3, 1 → 4, and 1 → 6 pyranose-furanose linkages and 2 → 1 and 2 → 6 furanose-furanose linkages, building on existing hexopyranose and furanose monosaccharide parameters. The model compounds were chosen to be monomers or glycosidic-linked dimers of tetrahydropyran (THP) and tetrahydrofuran (THF) as to contain the key atoms in full carbohydrates. Target data for optimization included two-dimensional quantum mechanical (QM) potential energy scans of the Φ/Ψ glycosidic dihedral angles, with geometry optimization at the MP2/6-31G(d) level followed by MP2/cc-pVTZ single-point energies. All possible chiralities of the model compounds at the linkage carbons were considered, and for each geometry, the THF ring was constrained to the favorable south or north conformations. Target data also included QM vibrational frequencies and pair interaction energies and distances with water molecules. Force field validation included comparison of computed crystal properties, aqueous solution densities, and NMR J-coupling constants to experimental reference values. Simulations of infinite crystals showed good agreement with experimental values for intramolecular geometries as well as for crystal unit cell parameters. Additionally, aqueous solution densities and available NMR data were reproduced to a high degree of accuracy, thus validating the hierarchically optimized parameters in both crystalline and aqueous condensed phases. The newly developed parameters allow for the modeling of linear, branched, and cyclic pyranose/furanose polysaccharides both alone and in heterogeneous systems including proteins, nucleic acids, and/or lipids when combined with existing additive CHARMM biomolecular force fields.