Structural Signatures of the O6-Methylguanine Lesion: A Multi-Method Feature Selection Analysis of Molecular Dynamics Simulations

Abstract O6-methylguanine (O6-meG) is a highly mutagenic DNA lesion, yet the structural signals that trigger its repair remain unclear. We performed molecular dynamics simulations of a library of O6-meG:C and G:C base paired dsDNA and introduced a statistical framework to identify key characteristics that distinguish the lesion from undamaged DNA. The simulations indicate significantly increased bending flexibility of O6-meG containing strands and show that the structural signature is localized to the lesion and not spread over flanking residues. Both the lesion and its base pair are disrupted in a manner that is largely independent of sequence, creating detectable structural signatures on both strands. This bilateral detectability may provide repair enzymes with redundant structural cues. By identifying key features from a large pool of descriptors, the employed analysis protocol may be more widely useful.