STRUCTURE AND BINDING FOR COMPLEXES OF REBEKS ACRIDINE DIACID WITH PYRAZINE, QUINOXALINE, AND PYRIDINE FROM MONTE-CARLO SIMULATIONS WITH AN ALL-ATOM FORCE-FIELD

The structures and relative binding free energies for complexes of pyrazine and pyridine with Rebek's acridine diacid in chloroform have been revisited through Monte Carlo statistical mechanics calculations at 25 degrees C. In order to further probe the reported selectivity of the host and to clarify the nature of binding benzo derivatives of pyrazine, computations were also carried out for quinoxaline. The calculations feature advances to a fully flexible all-atom model for the host. The guests, also represented by all-atom potential functions, were gradually mutated into one another both bound to the diacid and unbound in solution. Statistical perturbation theory (SPT) afforded the associated free energy changes, which combine to yield the relative free energies of binding. The experimentally observed binding order, quinoxaline > pyrazine > pyridine, was reproduced, and structures supporting two-point binding for the diazine guests were found. Energetic and structural comparisons with the earlier computational study are made, and the origin of the modest difference in binding pyrazine over pyridine is analyzed. An explanation for the enhanced binding of quinoxaline that does not include pi-stacking with the acridine spacer is provided, and the computed structures are compared with those hypothesized by Rebek as well as those recently published by Pascal and Ho.