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 (NCP), we report a robust MD-then-FO-DFTB/MM simulation protocol spanning 20 microseconds. Our work allows to identify several factors governing guanine ionization potential and to 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 might vary on the proximity of histone tails, so, on a biological point of view, on the chromatin state. SIGNIFICANCE The formation of guanine radicals cations is a hallmark in the realm of oxidative DNA damage. We situate the propensity to generate the guanine radical cation at specific positions of the nucleosome core particles owing to a tailored, systematic QM/MM computational protocol. Our approach affords a complementary look to recent experimental studies.