How methyl-sugar interactions determine DNA structure and flexibility

Korbinian Liebl, Martin Zacharias

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


The sequence dependent structure and flexibility of the DNA double helix is of key importance for gene expression and DNA packing and it can be modulated by DNA modifications. The presence of a C5′-methyl group in thymine or the frequent C5′-methylatedcytosine affects the DNA fine structure, however, the underlying mechanism and steric origins have remained largely unexplained. Employing Molecular Dynamics free energy simulations that allow switching on or off interactions with the methyl groups in several DNA sequences, we systematically identified the physical origin of the coupling between methyl groups and DNA backbone fine structure. Whereas methyl-solvent and methyl-nucleobase interactions were found to be of minor importance, the methyl group interaction with the 5′-neighboring sugar was identified as main cause for influencing the population of backbone substates. The sterical methyl sugar clash prevents the formation of unconventional stabilizing hydrogen bonds between nucleobase and backbone. The technique was also used to study the contribution of methyl groups to DNA flexibility and served to explain why the presence of methyl sugar clashes in thymine and methyl-cytosine can result in an overall local increase of DNA flexibility.

Original languageEnglish
Pages (from-to)1132-1140
Number of pages9
JournalNucleic Acids Research
Issue number3
StatePublished - 20 Feb 2019
Externally publishedYes


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