Revealing intrinsic changes of DNA induced by spore photoproduct lesion through computer simulation

In bacterial endospores, a cross-linked thymine dimer, 5-thyminyl-5,6-dihydrothymine, commonly referred to as the spore photoproduct (SP), is found as the dominant DNA photo lesion under UV radiation. During spore germination, SP is faithfully repaired by the spore photoproduct lyase (SPL) for normal DNA replication to resume. Despite this general mechanism, the exact way in which SP modifies the duplex DNA structure so that the damaged site can be recognized by SPL to initiate the repair process is still unclear. A previous X-ray crystallographic study, which used a reverse transcriptase as a DNA host template, captured a protein-bound duplex oligonucleotide containing two SP lesions; the study showed shortened hydrogen bonds between the AT base pairs involved in the lesions and widened minor grooves near the damaged sites. However, it remains to be determined whether the results accurately reflect the conformation of SP-containing DNA (SP-DNA) in its fully hydrated pre-repair form. To uncover the intrinsic changes in DNA conformation caused by SP lesions, we performed molecular dynamics (MD) simulations of SP-DNA duplexes in aqueous solution, using the nucleic acid portion of the previously determined crystal structure as a template. After MD relaxation, our simulated SP-DNAs showed weakened hydrogen bonds at the damaged sites compared to those in the undamaged DNA. Our analyses of the MD trajectories revealed a range of local and global structural distortions of DNA induced by SP. Specifically, the SP region displays a greater tendency to adopt an A-like-DNA conformation, and curvature analysis revealed an increase in the global bending compared to the canonical B-DNA. Although these SP-induced DNA conformational changes are relatively minor, they may provide a sufficient structural basis for SP to be recognized by SPL during the lesion repair process.