Molecular Dynamics Potential of Mean Force Calculations: A Study of the Toluene−Ammonium π-Cation Interactions

We have examined the interaction between the ammonium cation and the aromatic face of toluene in water, by means of potential of mean force (PMF) calculations. Considering that (i) typical two-body additive molecular mechanical models cannot represent the energetics of π-cation interactions accurately and (ii) employing nonadditive force fields increases the computational effort significantly, we have incorporated a short-range “10−12” term in our potential function, ensuring that the magnitude of the attraction between ammonium and toluene reproduces the value estimated from high-level quantum mechanical calculations. Interestingly, the PMF curve generated in water clearly demonstrates that association is favorable in a polar aqueous medium, with a minimum of the free energy equal to ca . 3 kcal/mol, and an association constant of 6.5 M -1 consistent with experimental data on related π-cation systems. This association appears to be even stronger when the approach of ammonium toward the toluene ring is axially constrained, hence indicating that, in addition to non-negligible entropic effects, the magnitude and the directionality of ammonium−aromatic interactions might be intimately related. A comparison of the free energy profiles obtained in a vacuum and in water suggests that “contact” configurations should be stabilized in nonpolar environments. This observation concurs with the analysis of Phe−Lys interactions in several protein crystal structures.