OpenCGChromatin, a high-performance near-atomistic coarse-grained model, reveals that linker DNA length controls chromatin phase separation through structural frustration: 10N+5 bp linkers introduce geometric frustration that exposes histone tails for multivalent inter-array interactions promoting condensate formation, while 10N bp linkers favor compact zigzag structures that sequester H4 and H2A N-terminal tails in intra-array contacts suppressing phase separation, with histone acetylation disrupting compaction in a pattern-specific manner through weakening of key tail-mediated interactions, particularly at H4K16 and H3K9.

Understanding how chromatin’s physicochemical properties shape its emergent organisation is central to deciphering genome function. To address this, we present OpenCGChromatin, a high-performance coarse-grained model that achieves near-atomistic simulations of chromatin systems an order of magnitude larger than previously possible, spanning biomolecular condensates and fibers tens of kilobases in length. OpenCGChromatin simulations independently predict, from physicochemical principles, the linker-DNA-dependent chromatin structures observed by cryo-ET and the relative thermodynamic stability of condensates inferred from biochemical assays. Crucially, OpenCGChromatin resolves histone-tail dynamics and interaction networks that remain inaccessible experimentally, explaining how linker-DNA length controls histone tail accessibility and the resulting multiscale structure of chromatin condensates. Extending simulations to 108-nucleosome fibers shows that acetylation disrupts chromatin compaction in a pattern-specific manner by weakening key tail-mediated interactions, with H4K16 and H3K9 emerging as the most energetically disruptive modifications. These results position OpenCGChromatin as a powerful framework for linking molecular detail to emergent chromatin organization.