Carbohydrates: United atom AMBER* parameterization of pyranoses and simulations yielding anomeric free energies

The success of molecular modeling using classical potential functions (i.e force field calculations) rests heavily on the availability of specific, high-quality parameters that accurately describe the gas phase potential surface of the molecular system under study, on solvent models that reliably reproduce the effect of the medium, and on simulation methods that sample all significantly populated conformations of the entire system with the correct statistical weights. In this paper we present a set of molecular mechanics parameters that were developed using ab initio molecular orbital calculations to model pyranoses in the context of the AMBER* force field in the molecular modeling package MacroModel 5.0. These parameters were tailored to reproduce the quantum mechanical conformational energies of certain small molecules that were taken as models for common substructures in monosaccharides. Solvent was included as the GB/SA continuum model for water. The sampling problem was solved for these systems using the recently described MC(JBW)/SD simulation method that facilitates interconversion of predetermined conformational minima by alternating between smart Monte Carlo and stochastic dynamics steps. A series of such MC(JBW)/SD stimulations using the new carbohydrate parameters was used to calculate anomeric α,β ratios (and thus anomeric free energy differences) for tetrahydropyran derivatives and the pyranose monosaccharides glucose, methyl glucoside, mannose, methyl mannoside, galactose, 2-deoxyglucose, and N-acetylglucosamine. In all cases, the simulations converged within 1 ns to yield anomeric free energies that are within 0.4 kcal/mol of the experimentally determined anomeric free energies in water.