Contributions of the thymine methyl group to the specific recognition of poly- and mononucleotides: an analysis of the relative free energies of solvation of thymine and uracil.

Experimental results indicate that interactions with the 5-methyl group of thymine often account for around 1 kcal/mol of the total selectivity at A.T base pairs in protein-DNA complexes. The limited ability of methyl groups to form noncovalent interactions of this magnitude has led to the hypothesis that the energy of solvation of this hydrophobic element is responsible for the observed contribution to selectivity; however, it has not been possible to test this experimentally. We report a molecular dynamics perturbation thermodynamics (MD/PT) analysis of the relative free energy of solvation of thymine and uracil, both as the free bases and in the context of double-stranded DNA. The use of MD/PT indicates that the effect of shielding the 5-methyl group from solvent accounts for 0.90 +/- 0.11 kcal/mol of the observed contribution to specificity in protein-DNA complexes. We suggest some implications of these results for the mechanism of sequence-specific DNA recognition, DNA structure, and the evolution of the deoxynucleotide synthesis pathways.