CONFORMATION AND DYNAMICS OF ALKYLATED BASES WITHIN DNA - EFFECT OF METHYL ROTATION

Alkylation of thymine and guanine bases leads to mutations unless thes e lesions are repaired by a protein, DNA-alkyltransferase. Molecular d ynamics simulations over 1000 ps have been used to study the conformat ion of the extra methyl group and to monitor any changes in local or g lobal 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 O-4-methylthymi ne, the methyl group adopts the distal conformation, pointing towards the opposing base whatever the starting conformation, and thus the fin al geometry of the modified base-pair is not dependent on the starting conformation of the methyl group. In O-6-methylguanine, the methyl gr oup stays in its initial conformation in the plane of the base, pointi ng 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 a s well as increased curvature in the vicinity of modified base.