Potential of Mean Force for the Isomerization of DMF in Aqueous Solution: A Monte Carlo QM/MM Simulation Study

Potential of mean force for the isomerization of a tertiary peptide bond in N,N-dimethylformamide (DMF) is determined using a combined quantum mechanical and molecular mechanical (QM/MM) potential in Monte Carlo simulations. Both the anti and syn transformations were considered. The computed free energy of activation in the gas phase is 19.8 kcal/mol for the anti transition state and 20.2 kcal/mol for the syn form. This is in excellent agreement with the gas-phase NMR measurements (19.4 ± 0.1 kcal/mol). The solvent effects were found to nicely mirror the change of dipole moment for DMF in water, with predicted solvation destabilizations of the transition states by 2.7 ± 0.2 and 0.5 ± 0.1 kcal/mol for the anti and syn forms, respectively. The results are in accord with previous theoretical studies of N,N-dimethylacetamide (DMA) in water and CCl₄ by Duffy et al. The computed free energy of activation (20.8 kcal/mol) in water is consistent with experimental findings for DMF in pure liquid and other solvents. In addition, the finding that DMF was polarized more favorably in the ground states than the rotamers suggests that it is necessary to include explicit polarization terms in empirical potential functions for fluid simulations.