Anharmonic vibrational self-consistent field calculations as an approach to improving force fields for monosaccharides

An Amber-type of force field, based on experimental vibrational frequencies which is suitable for monosaccharides. is presented. In the present force field, the atomic partial charges and some torsional parameters are derived from a fit of calculated vibrational energy levels to known experimental s pectra for alpha-D-glucose. The vibrational spectra were calculated using t he vibrational self-consistent field (VSCF) method, which includes contribu tions from both anharmonic and mode-coupled terms. We find that with a repa rametrization of the force field the agreement between the experimental and calculated vibrational spectra is +/-3.3 cm(-1) for alpha-glucose and +/-5 .1 cm(-1) for beta-glucose. Using the VSCF method, we an also able to lend support to the idea that the COH bending motion is strongly coupled to the methylene and methine modes, as well as the other internal modes. We then t est our spectroscopically derived force field by calculating the anomeric e ffect for alpha --> beta glucose. Molecular dynamics simulations are perfor med separately for both anomers (alpha and beta) in order to evaluate confi gurational entropy, and hence free energy. We find that out of six simulati ons. half correctly predict the anomeric free energy Delta G(alpha-->beta) = -0.3 kcal/mol, while two simulations yield a Delta G(alpha-->beta) = +0.2 kcal/mol, and in one simulation Delta G(alpha-->beta) similar to 0.0 kcal/ mol. We also calculate the atomic pair distribution function, g(r), and sho w that in most simulations, the beta-conformer is slightly more adept at st ructuring the surrounding water molecules, resulting in better hydrogen bon ding fur this anomer. However, we believe that our force field, which is st atic, is unable to represent adequately the dynamic interactions between th e pyranose sugar and the surrounding water molecules. This resulted in a la rge fluctuation about the average calculated anomeric free energy of Delta G(alpha-->beta) similar to -0.1 kcal/mol. Thus, while the current all atom force field is well suited for spectroscopic studies of monosaccharides, it is not yet well suited for dynamical studies.