Molecular features underlying phase separation of protein-nucleic acid condensates revealed by a new coarse-grained DNA model

Recent advances in residue-level coarse-grained (CG) computational models for proteins have enabled molecular-level insights into the properties of protein condensates. However, most of the existing CG nucleic acid models include anisotropic potentials between bases that are computationally demanding and are not fully compatible with the existing CG protein models. Here, we present a new CG DNA model that utilizes isotropic potentials between bases and can be used for investigating protein-DNA complexes and nucleosome arrays, thereby enabling a mechanistic understanding of how molecular information is propagated up at the genome level in a computationally tractable manner. To demonstrate the suitability of our model to facilitate large-scale simulations with a molecular resolution, we simulate nucleosomes (mono, di, etc.) to generate equilibrium conformational ensembles. The simulation data provide essential insights into the role of chromatin in the liquid-liquid phase separation of HP1α protein. We find an extensive network of interactions between HP1α, DNA, and flexible histone tails in the condensates formed by these different biomolecules. The findings of this work illuminate the complex molecular framework that contributes to heterochromatin regulation and function.