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J. Biol. Chem., Vol. 277, Issue 32, 28491-28497, August 9, 2002

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The Influence of the Thymine C5 Methyl Group on Spontaneous Base Pair Breathing in DNA^*

Sebastian Wärmländer, Judit E. Sponer^§, Jii Sponer^§¶, and Mikael Leijon^**

From the  Department of Biochemistry and Biophysics, Arrhenius Laboratory, Stockholm University, S-106 91 Stockholm, Sweden, the ^§ J. Heyrovský Institute of Physical Chemistry, Academy of Sciences of the Czech Republic, Dolejkova 3, 182 23 Prague 8, Czech Republic, and the ^¶ Institute of Biophysics and National Center for Biomolecular Research, Academy of Science of the Czech Republic, Kralovopolska 135, 612 65 Brno, Czech Republic

Sequences of four or more AT base pairs without a 5'-TA-3' step, so-called A-tracts, influence the global properties of DNA by causing curvature of the helix axis if phased with the helical repeat and also influence nucleosome packaging. Hence it is interesting to understand this phenomenon on the molecular level, and numerous studies have been devoted to investigations of dynamical and structural features of A-tract DNA. It was early observed that anomalously slow base pair-opening kinetics were a striking physical property unique to DNA A-tracts (Leroy, J. L., Charretier, E., Kochoyan, M., and Gueron, M. (1988) Biochemistry 27, 8894-8898). Furthermore, a strong correlation between DNA curvature and anomalously slow base pair-opening dynamics was found. In the present work it is shown, using imino proton exchange measurements by NMR spectroscopy that the main contribution to the dampening of the base pair-opening fluctuations in A-tracts comes from the C5 methylation of the thymine base. Because the methyl group has been shown to have a very limited effect on the DNA curvature as well as the structure of the DNA helix, the thymine C5 methyl group stabilizes the helix directly. Empirical potential energy calculations show that methylation of the tract improves the stacking energy of a base pair with its neighbors in the tract by 3-4 kcal/mol.

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