Contribution of Opening and Bending Dynamics to Specific Recognition of DNA Damage

Guanine-uracil (G·U) wobble base-pairs are a detrimental lesion in DNA. Previous investigations have shown that such wobble base-pairs are more prone to base-opening than the normal G·C base-pairs. To investigate the sequence-dependence of base-pair opening we have performed 5 ns molecular dynamics simulations on G·U wobble base-pairs in two different sequence contexts, TGT/AUA and CGC/GUG. Furthermore, we have investigated the effect of replacing the guanine base in each sequence with a fluorescent guanine analogue, 6-methylisoxanthopterin (6MI). Our results indicate that each sequence opens spontaneously towards the major groove in the course of the simulations. The TGT/AUA sequence has a greater proportion of structures in the open state than the CGC/GUG sequence. Incorporation of 6MI yields wobble base-pairs that open more readily than their guanine counterparts. In order of increasing open population, the sequences are ordered as CGC