A Quantum Mechanically Derived All-Atom Force Field for Pyranose Oligosaccharides. AMBER* Parameters and Free Energy Simulations

In this paper we extend our previously reported parameterization of carbohydrates to an all-atom AMBER-like force field suitable for modeling oligosaccharides. Parameters were developed from ab initio calculations on small model systems having structures characteristic of 1,2-, 1,3-, and 1,4-glycosidic linkages and monosaccharides to give a complete parameter set for pyranose mono- and oligosaccharides. The accuracy of the parameter set was assessed by free energy calculations on various simple sugars and disaccharides. Solvent effects were included using the GB/SA continuum model for water. The sampling problem was solved for these systems by the recently described MC/SD and MC(JBW)/SD simulation methods that facilitate interconversion of conformational states. MC(JBW)/SD simulations were used to calculate anomeric free energies for tetrahydropyran derivatives and monosaccharides. All simulations rapidly converged to values in good agreement with the experimental results. MC/SD simulations were used to study the conformational free energies of selected disaccharides in water. In all cases, our free energy simulations generally reproduced the known conformational features of these systems, namely, the preference of the glycosidic angle (φ) for the exo-anomeric conformation and the aglyconic angle (ψ) for the syn conformation. All of the disaccharides spent >98% of their time in a single conformational energy well corresponding to the syn, exo-anomeric conformer, though the interresidue φ and ψ torsion angles fluctuated considerably in aqueous solution at rt. 3JC,H coupling constants across the glycosidic and aglyconic linkages were calculated using a Karplus-like equation with the distributions of the appropriate torsional angles and show reasonable agreement with the experimental data. Experimental NOE data were also semiquantitatively reproduced. X-ray structures of the disaccharides were found to correspond to populated regions of the simulated φ and ψ angular distribution maps.