ACETYLCHOLINE RECOGNITION BY AN AROMATIC HOST - THE ROLE OF AN ALL-HYDROGEN TOPOLOGY IN SIMULATIONS OF THE CATION-PI INTERACTION

The contribution of cation-pi interactions to the affinity of a synthe tic aromatic host for acetylcholine in a molecular mechanics simulatio n was estimated using a thermodynamic cycle-free energy perturbation a pproach. Compared to a host in which aromatic dipole ring charges were set to zero, the affinity of the host for acetylcholine is greater by 1.8 kcal/mole when using a set of typical simulation parameters. The role of four ether oxygens in the host is probably negligible. Althoug h acetylcholine binding may be driven in large part by hydrophobic eff ects, cation-pi interactions most likely make a significant contributi on to the selectivity of this host for quaternary ammonium cations.