Histone H3 cysteines as redox switches in the nucleosome: molecular modeling of S-sulfenylation and its structural consequences

In the nucleosome core particle, S-sulfenylation of histone H3 cysteines C96 and C110 is enabled by hydrophobic shielding and a nearby base, with ~12 kcal/mol barriers.

• Why it matters: Oxidation of buried histone cysteines is linked to redox signaling and chromatin regulation, but how H2O2 reaches these protected thiols and how modifications reshape nucleosomes was unknown.
• What they did: Using all-atom molecular dynamics, QM/MM, and free-energy calculations, the study modeled oxidant access and structural effects for both H3.1 C96 and shared H3 C110, including entry routes and reorganization steps.
• The result: Oxidizing either cysteine costs ~12 kcal/mol, with ~18 kcal/mol barriers for C96 and C110 reorganization; C96 modification targets DNA-histone interfaces and remodeler/chaperone elements, while C110 oxidation mainly favors dyad unwrapping and DNA destabilization.

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