Abstract
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′-methylated-cytosine 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.
Highlights
The structure and flexibility of double-stranded DNA and the binding of proteins is influenced by the nucleic acid backbone structure [1,2,3]
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
The Molecular Dynamics (MD) simulations indicate that the presence of methyl groups at the C5 of pyrimidines in DNA stabilizes the BI backbone states
Summary
The structure and flexibility of double-stranded DNA and the binding of proteins is influenced by the nucleic acid backbone structure [1,2,3]. One of the most prominent conformational polymorphism in DNA is due to two different combinations of the ⑀ and dihedral angles in nucleotides adopting either the canonical BI (⑀/ in the trans/ gauche-) or BII configuration (⑀/ in the gauche-/trans, Figure 1). These substates contribute to the bimodal distribution of a base-pair step’s twist, are significantly affected by mechanical stress and are coupled to the dimensions of minor and major groove [4,5,6,7]. In principle, all purines and pyrimidines in DNA can form such contacts based on the same sterical and geometrical reasons, the observed correlation does not offer a direct sterical explanation
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
