Charge-altering histone mutations reprogram electrostatic coupling from single nucleosomes to higher-order chromatin structures

Nucleosomes are stabilized and organized by electrostatic interactions that govern chromatin folding and higher-order structure. Although many cancer-associated histone mutations alter residue charge, how such perturbations propagate from single nucleosomes to higher-order chromatin organization remains unclear. Here, through large-scale analysis of histone mutation datasets, we show that charge-altering mutations are enriched among recurrent high-frequency mutations and exhibit stronger predicted destabilizing effects on nucleosome-associated interactions than charge-neutral variants. We demonstrate that even a single charge-altering mutation can substantially reshape the nucleosome surface electrostatic potential, thereby modulating long-range electrostatic interactions with regulatory proteins. By systematically analyzing 25 experimentally resolved nucleosome-protein complexes and 183 mutant models, we quantify how individual charge-altering mutations substantially alter electrostatic interaction forces. Extensive molecular dynamics simulations totaling 18 μs further reveal that single-point mutations can produce less favorable nucleosome-protein binding-energy estimates and reorganize interfacial hydrogen-bonding networks. Importantly, analysis of higher-order nucleosome assemblies shows that charge-altering mutations can modulate inter-nucleosomal electrostatic interactions in a packing-geometry-dependent manner, while mutations near the acidic patch can also perturb H4 tail-nucleosome electrostatic coupling. Our results provide a physical framework for understanding how local electrostatic perturbations caused by cancer-associated charge-altering histone mutations may influence nucleosome interactions across multiple structural scales.