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Published March 15, 1994 | metadata_only
Journal Article

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.

Additional Information

© 1994 American Chemical Society. Published in print 15 March 1994. Contribution No. 8854 from the Division of Chemistry and Chemical Engineering, Caltech. This work was supported by a grant from the Advanced Industrial Concepts Division (AICD) of the Department of Energy (DOE). K.W.P.h as been supported in part by a National Science Foundation graduate fellowship. The KSR computer facilities were supported by NSF-GCAG (ASC-9217368). The facilities of the MSC are also supported by grants from NSF Chemistry (91-00284), DOECB, Allied-Signal, Asahi Chemical, Asahi Glass, BP Chemical, Chevron, BF Goodrich, Vestar, Teijin, and Xerox. We thank Dr. Murco N. Ringnalda (Schrodinger) for performing the PS-GVB calculations used in this study and Dr. Steve Benner (ETH, Zurich) for suggesting the role of solvation in stabilizing the double helix. We wish to thank Dr. Steve Breit of Kendall Square Research for help in optimizing the MD/PT code. The simulations were carried out on the KSR in the MSC and on the KSR at the NSFCornell Supercomputer Center.

Additional details

August 20, 2023
August 20, 2023