SOLVATION FREE-ENERGIES OF SMALL AMIDES AND AMINES FROM MOLECULAR-DYNAMICS FREE-ENERGY PERTURBATION SIMULATIONS USING PAIRWISE ADDITIVE ANDMANY-BODY POLARIZABLE POTENTIALS

Molecular dynamics/free energy perturbation simulations of several sma ll amides [acetamide (ACT), N-methylacetamide (NMA), and N,N-dimethyla cetamide] and amines [NH3, NH2CH3, NH(CH3)(2), and N(CH3)(3)] in aqueo us solution were performed to study the effects on solvation free ener gies arising from N-methylation. Using pairwise additive potentials, a uniform pattern of solvation effects was always obtained, indicating that successive substitution of hydrogens on the nitrogen atom by hydr ophobic methyl groups leads to less favorable solvation. These results are not in agreement with experimental data, which show that the solv ation free energy changes associated with N-methylation are irregular and actually favor methylation in the cases of ACT --> NMA and NH3 --> NH2CH3. The amines were also studied using a many-body polarizable po tential for both the solute and the solvent. The resulting salvation f ree energy differences represent improvements over the values obtained with the pairwise additive potentials, although the monotonic change in solvation free energy with increasing methylation persists. With th e many-body polarizable potential, the magnitudes of the amine dipole moments in aqueous solution exhibit the same trend as the solvation fr ee energies. This observation provides a basis for understanding the i rregular behavior of the experimental amine solvation free energies.