OPLS POTENTIAL FUNCTIONS FOR NUCLEOTIDE BASES - RELATIVE ASSOCIATION CONSTANTS OF HYDROGEN-BONDED BASE-PAIRS IN CHLOROFORM

Potential functions in the OPLS format have been developed for the nucleotide bases and 2,6-diaminopyridine by fitting to the results of ab initio 6-31 G(d) calculations for numerous base-water complexes. These potential functions yield dipole moments and base pair interaction energies in good agreement with available experimental data. The potential functions were tested further in Monte Carlo simulations with statistical perturbation theory to calculate the relative free energies of binding in chloroform for 9-methylguanine with 1-methylcytosine (G-C) versus 9-methyladenine with 1-methyluracil (A-U), and for G-C versus 1-methyluracil with 2,6-diaminopyridine (U-DAP). The calculations predict the G-C complex to be more stable than both the A-U and U-DAP complexes by about 5 kcal/mol. The similar stabilities for complexes like A-U and U-DAP are observed experimentally, though the quantitative enhancement in going to G-C appears to be exaggerated in the simulations. The large difference in association constants between G-C and the similarly triply hydrogen-bonded U-DAP is traced to the gas-phase interaction energies, which favors G-C by about 10 kcal/mol. This in turn is caused by the different arrangement of hydrogen bond donor and acceptor sites in the two complexes, which leads to secondary electrostatic interactions that disfavor U-DAP relative to G-C. The general importance of such secondary interactions for understanding variations in association is discussed.