MOLECULAR-DYNAMICS POTENTIAL OF MEAN FORCE CALCULATIONS - A STUDY OF THE TOLUENE-AMMONIUM PI-CATION INTERACTIONS

We have examined the interaction between the ammonium cation and the a romatic face of toluene in water, by means of potential of mean force (PMF) calculations. Considering that (i) typical two-body additive mol ecular mechanical models cannot represent the energetics of pi-cation interactions accurately and (ii) employing nonadditive force fields in creases the computational effort significantly, we have incorporated a short-range ''10-12'' term in our potential function, ensuring that t he 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 t hat association is favorable in a polar aqueous medium, with a minimum of the free energy equal to ca. 3 kcal/mol, and an association consta nt of 6.5 M(-1)-consistent with experimental data on related pi-cation systems. This association appears to be even stronger when the approa ch of ammonium toward the toluene ring is axially constrained, hence i ndicating that, in addition to non-negligible entropic effects, the ma gnitude and the directionality of ammonium-aromatic interactions might be intimately related. A comparison of the free energy profiles obtai ned in a vacuum and in water suggests that ''contact'' configurations should be stabilized in nonpolar environments. This observation concur s with the analysis of Phe-Lys interactions in several protein crystal structures.