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
simulations 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.