What tunes guanine ionization potential in a nucleosome? An all-in-one systematic QM/MM assessment

Guanine radical cations are precursors to oxidatively induced DNA lesions, and the determination of oxidative DNA hot spots beyond oligonucleotides remains a current challenge. In order to rationalize the finetuned ionization properties of the ∼60 guanines in a nucleosome core particle, we report a robust molecular dynamics-then-FO-DFTB/MM (fragment-orbital tight-binding density functional theory/molecular mechanics) simulation protocol spanning 20 μs. Our work allows us to identify several factors governing guanine ionization potential and map oxidative hotspots. Our results highlight the predominant role of the proximity of positively charged histone residues in the modulation of the guanine ionization potential up to 0.6 eV. Consequently, fast, long-range hole transfer in nucleosomal DNA could be tuned by the proximity of histone tails, which differs, from a biological point of view, on the chromatin state.