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

Abstract

Oxidation of buried histone cysteines links cellular redox signaling to chromatin regulation. Histone H3 carries two such residues: C96, unique to the H3.1 variant, and C110, shared by most H3 variants. Oxidation of H3.1 C96 by H2O2 drives histone variant exchange and chromatin opening in cancer cells, and C110 undergoes S-glutathionylation, yet both thiols are shielded from the solvent. How they are oxidized and what the modification does to the nucleosome structure remain unknown. Combining all-atom molecular dynamics, QM/MM and free energy calculations, we reveal S-sulfenylation mechanisms at both cysteines within the nucleosome core particle, from oxidant access to its structural consequences. Reaching either cysteine costs ~12 kcal/mol, paid mostly for the desolvation of H2O2 independently of the entry route. The reaction is then enabled in the hydrophobic environment by the presence of a single neighboring base. Such a residue is already in place at C110 (H3D123), but must first reorganize at C96 (H3E97), with barriers of ~18 kcal/mol at both sites. Once formed, the modification acts well beyond its site. C96 S-sulfenylation acts on DNA-histone interfaces, on elements recognized by chromatin remodelers and chaperones (H2AE91 at the acidic patch, H2A C-term release), and on the H4K91-H2B'D68 salt bridge bridging the two halves of the nucleosome. C110 oxidation mainly favors unwrapping and DNA destabilization at the dyad. These results provide a structural framework for understanding histone-mediated redox signaling and its implication in chromatin remodeling.