Systematic assessment of the flexibility of uracil damaged DNA

Uracil is a common DNA lesion which is recognized and removed by uracil DNA-glycosylase (UDG) as a part of the base excision repair pathway. Excision proceeds by base flipping, and UDG efficiency is thought to depend on the ease of deformability of the bases neighboring the lesion. We used molecular dynamics simulations to assess the flexibility of a large library of dsDNA strands, containing all tetranucleotide motifs with U:A, U:G, T:A or C:G base pairs. Our study demonstrates that uracil damaged DNA largely follows trends in flexibility of undamaged DNA. Measured bending persistence lengths, groove widths, step parameters and base flipping propensities demonstrate that uracil increases the flexibility of DNA, and that U:G base paired strands are more flexible than U:A strands. Certain sequence contexts are more deformable than others, with a key role for the 3' base next to uracil. Flexibilities are large when this base is an A or G, and repressed for a C or T. A 5' T adjacent to the uracil strongly promotes flexibility, but other 5' bases are less influential. DNA bending is correlated to step deformations and base flipping, and bending aids flipping. Our study implies that the link between substrate flexibility and UDG efficiency is widely valid, helps explain why UDG prefers to bind U:G base paired strands, and suggests that the DNA bending angle of the UDG-substrate complex is optimal for base flipping.Communicated by Ramaswamy H. Sarma.