Calculation of chloroform/water partition coefficients for the N-methylated nucleic acid bases

The chloroform/water partition coefficients have been determined for five 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 using 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 free energies. Two separate sets of chloroform simulations were performed differing only in the choice of atomic charges for chloroform and the bases. In the first simulations, labeled as charge set 1 (CS1), RESP was used with the RHF/6-31G(3dt,2p) basis set to determine the chloroform charges and the RHF/6-31G(*) basis set to determine the charges for the nucleic acid bases. For the second simulations, labeled as charge set 2 (CS2), the CS1 chloroform charges were scaled down to reproduce the experimental dipole moment in solution, and the CS1 bases charges were reduced by 10%. The reduction of the atomic charges in the second model was done to account for the less polarizing environment of chloroform (as compared to water) and yielded a significant improvement in the calculated results. The partition coefficients calculated from CS1 yielded an average absolute error of 1.5 log units compared to experiment, where in contrast, CS2 shows good agreement, with an average absolute error of only 0.5 log units.