Conformation and dynamics of alkylated bases within DNA: effect of methyl rotation

Abstract

Alkylation of thymine and guanine bases leads to mutations unless these lesions are repaired by a protein, DNA-alkyltransferase. Molecular dynamics simulations over 1000 ps have been used to study the conformation of the extra methyl group and to monitor any changes in local or global structure of the DNA which may be used to recognise it prior to repair. The behaviour of the methyl group itself is very different for alkylated guanine compared with alkylated thymine. In O⁴-methylthymine, the methyl group adopts the distal conformation, pointing towards the opposing base whatever the starting conformation, and thus the final geometry of the modified base-pair is not dependent on the starting conformation of the methyl group. In O₆-methylguanine, the methyl group stays in its initial conformation in the plane of the base, pointing either towards (distal) or away from (proximal) the opposing base. This leads to changes in the local conformation of the base-pair with more disruption when the methyl group adopts the distal conformation as well as increased curvature in the vicinity of modified base.