CHARMM Drude Polarizable Force Field for Glycosidic Linkages Involving Pyranoses and Furanoses

Abstract

We present an extension of the CHARMM Drude polarizable force field to enable modeling of polysaccharides containing pyranose and furanose monosaccharides. The new force field parameters encompass 1↔2, 1→3, 1→4, and 1→6 pyranose-furanose linkages, 2→1 and 2→6 furanose-furanose linkages, 2→2, 2→3, and 2→4 furanose-pyranose, and 1↔1, 1→2, 1→3, 1→4, and 1→6 pyranose-pyranose linkages. For the glycosidic linkages, both simple model compounds and the full disaccharides with methylation at the reducing end were used for parameter optimization. The model compounds were chosen to be monomers or glycosidic-linked dimers of tetrahydropyran (THP) and tetrahydrofuran (THF). Target data for optimization included one- and two-dimensional potential energy scans of ω and the Φ/Ψ glycosidic dihedral angles in the model compounds and full disaccharides computed by quantum mechanical (QM) RIMP2/cc-pVQZ single point energies on MP2/6-31G(d) optimized structures. Also included in the target data are extensive sets of QM gas phase monohydrate water-saccharide interactions, dipole moments, and molecular polarizabilities for both model compounds and full disaccharides. The resulting polarizable model is shown to be in good agreement with a range of QM data, offering a significant improvement over the additive CHARMM36 carbohydrate force field, as well as experimental data including crystal structures and conformational properties of disaccharides and a trisaccharide in aqueous solution.

Figure 1

Model compounds MC1, MC3, MC4, MC5 and MC6 that were used to parametrize the glycosidic linkage in pyranose-furanose and furanose-furanose disaccharides (MC1 for p1→2f, MC3 for p1→3/4f, MC4 for f2→2/3/4p, MC5 for f2→6f, and MC6 for p1→6f).

Figure 2

Model compounds MC10 and MC11 that were used to parametrize the glycosidc linkages in the pyranose-pyranose disaccharides. (MC10 for p1→1p and MC11 for p1→2/3/4p)

Figure 3

Model compound root mean square errors (RMSE) of relative conformational energies between the QM and MM results. Energies in kcal/mol. Fitted indicates RMSE using final optimized parameter of the model compounds and and Zero indicates RMSE using the target dihedral parameters set to zero. Data presented in Supplement Table S9.

Figure 4

Φ/Ψ Potential energy surfaces in the QM and MM representations for the 4 anomers (αα, αβ, βα and ββ) of pyranose-furanose model MC1 used to optimize dihedral parameters associated with 1→2 glycosidic linkages. Results are presented for the five membered (THF) ring constrained to either south (left two columns) or north (right two columns) conformations and the four anomeric types are shown in the difference rows. Energies are in kcal/mol with contours every 1 kcal/mol.

Figure 5

Full disaccharide root mean square error (RMSE) of relative conformational energies between the QM and MM results for the pyrans. Energies in kcal/mol. Data presented in supporting information Table S10. Drude (full) and (model) indicates parameters optimized based on full disaccharides and the THP/THF model compound QM target data, respectively. The dashed lines demarcates the pyranose-furanose/aldopentose disaccharides to the left and the pyranose-pyranose disaccharides to the right.

Figure 6

Φ/Ψ potential energy surfaces in the QM and MM (fit) representations for the p1→4p anomers (αα, αβ, βα, ββ) of the full sugar. Results are presented for QM, Drude and additive force field across rows. Energies are in kcal/mol with contours every 1 kcal/mol. In the additive βα panel, the energies are all > 12 kcal/mol, such that the panel is completely blank.