Free Energy Landscape\nof Lesion Recognition by Human\n8‑Oxoguanine DNA N‑Glycosylase 1: Mechanistic Insights\ninto Detection and Processing of 8‑Oxoguanine in DNA

Human 8-oxoguanine DNA <i>N</i>-glycosylase\n1 (hOGG1)\nis an essential enzyme in DNA repair, responsible for recognizing\nand excising 8-oxoguanine (8OG), the lesion resulting from oxidative\ndamage to guanine (G). By removing 8OG, hOGG1 prevents mutations like\nG-to-T transversions, maintains genomic stability, and reduces the\nrisk of cancer and other diseases. Structural studies of hOGG1 bound\nto DNA have shown that lesion recognition occurs through base eversion\nfrom the DNA helix and hOGG1 finger residue insertion into the DNA\nhelix. To better understand this complex process, enhanced sampling\nmolecular dynamics simulations were used to map two-dimensional free\nenergy surfaces that describe lesion recognition in terms of base\neversion and finger residue insertion. The resulting free energy profiles\nreveal one major SN2-like and two minor SN1-like pathways for 8OG\nand normal G and show that hOGG1 has kinetic and thermodynamic advantages\nin terms of recognizing 8OG over G. Based on these data, simple kinetic\nmodels were utilized to provide a quantitative view of lesion recognition\nkinetics of 8OG versus G. The most favorable kinetic scenario identified\nwas that the scanning rate of hOGG1 falls between the initial interrogation\nrates of 8OG and G. According to this scenario, hOGG1 rapidly scans\nnormal Gs at its intrinsic diffusion speed, bypassing unnecessary\ninterrogations. However, when hOGG1 encounters 8OG, the enzyme significantly\nslows down during lesion recognition until the damaged base is excised\nfrom its catalytic pocket. This highly selective mechanism ensures\nthat hOGG1 efficiently repairs oxidative DNA damage by carefully regulating\nhow it scans the DNA, thus optimizing the balance between speed and\naccuracy during the scanning process.