Evaluation of the Molecular Configuration Integral in All Degrees of Freedom for the Direct Calculation of Conformational Free Energies: Prediction of the Anomeric Free Energy of Monosaccharides

A novel theoretical approach is presented for the direct calculation of conformational free energies without the need for expensive free energy simulations and the use of computational alchemy. It is shown that conformational search combined with advanced Monte Carlo integration can tackle the daunting problem of solving the molecular configuration integral in all degrees of freedom, affording a direct method to calculate accurate conformational free energies. The new algorithm termed mode integration (MINTA) was applied here to explain anharmonic effects in cycloheptane and to predict the A value of cyclohexane derivatives and the anomeric free energy of carbohydrates (tetrahydropyran derivatives and pyranose monosaccharides) using a continuum solvation model.