On the use of electrostatic potential derived charges in molecular mechanics force fields. The relative solvation free energy of cis‐ and trans‐N‐methyl‐acetamide

Abstract We have carried out free energy perturbation calculations on the relative solvation free energy of cis ‐ and trans ‐ N ‐methyl‐acetamide (NMA). Experimentally, the solvation free energy difference has been found to be near zero. Using 6‐31G* ab initio electrostatic potential derived charges for both the cis and trans conformations, we calculate a solvation free energy difference of 0.1 ± 0.1 kcal/mol. Using the 6‐31G* charges derived for the trans conformation for both the cis and trans models leads to a solvation free energy difference of 0.9 ± 0.1 kcal/mol, compared to the value of 2.2 kcal/mol determined for the OPLS model for trans ‐NMA.