CALCULATION OF CHLOROFORM WATER PARTITION-COEFFICIENTS FOR THE N-METHYLATED NUCLEIC-ACID BASES/

The chloroform/water partition coefficients have been determined for f ive N-methylated nucleic acid bases (9-methyladenine, 9-methylguanine, 1-methylcytosine, 1-methythymine, and 1-methyluracil) by calculating the absolute solvation free energies of the bases in chloroform and us ing the data for water calculated previously by Miller and Kollman (J. Phys. Chem. 1996, 100, 8587). Thermodynamic perturbation calculations with explicit solvent were used to determine the absolute solvation f ree energies. Two separate sets of chloroform simulations were perform ed differing only in the choice of atomic charges for chloroform and t he bases. In the first simulations, labeled as charge set 1 (CS1), RES P was used with the RHF/6-31G(3dt,2p) basis set to determine the chlor oform charges and the RHF/6-31G() basis set to determine the charges for the nucleic acid bases. For the second simulations, labeled as cha rge set 2 (CS2), the CS1 chloroform charges were scaled down to reprod uce the experimental dipole moment in solution, and the CS1 bases char ges were reduced by 10%. The reduction of the atomic charges in the se cond model was done to account for the less polarizing environment of chloroform (as compared to water) and yielded a significant improvemen t in the calculated results. The partition coefficients calculated fro m CS1 yielded an average absolute error of 1.5 log units compared to e xperiment, where in contrast, CS2 shows good agreement, with an averag e absolute error of only 0.5 log units.