Nucleosome plasticity is a critical element of chromatin liquid-liquid phase separation and multivalent nucleosome interactions

Liquid-liquid phase separation (LLPS) of chromatin is an important mechanism that helps explain the membrane-less compartmentalization of the nucleus. Because chromatin compaction and LLPS are collective phenomena, linking their modulation to biophysical features of individual nucleosomes is challenging. Here, we develop a novel multiscale chromatin model that integrates atomistic representations, a chemically-specific coarse-grained model, and a minimal model. In tandem, we devise a transferable Debye-length exchange molecular dynamics approach to achieve enhanced sampling of high-resolution chromatin. We find that nucleosome thermal fluctuations become significant at physiological salt concentrations and destabilize the 30-nm fiber. Nucleosome breathing favors stochastic folding of chromatin and promotes LLPS by simultaneously boosting the transient nature and heterogeneity of nucleosome-nucleosome contacts, and the effective nucleosome valency. Our results put forward the intrinsic plasticity of nucleosomes as a key element in the liquid-like behavior of chromatin, and help reconcile longstanding differences between fiber-based and in vivo chromatin models.