(525a) Revealing the Dynamic Coupling between Protein and DNA in Heterochromatin Condensates Using Physics-Based Computational Models

Protein-DNA binding can significantly impact DNA structure and the resulting DNA structure can regulate the dynamics of protein binding. Many DNA binding proteins are known to exhibit two modes of motion, namely diffusion through sliding and pausing along the DNA, that are intricately coupled to the extent of DNA’s local compaction (i.e., DNA bending). However, it is not clear whether such dynamical behaviors at the molecular scale have relevance in dictating the mesoscopic dynamics and macroscopic material properties of protein-DNA condensates. In that regard, heterochromatin protein 1α (HP1α) plays a significant role in genome organization by binding to DNA and compacting it, leading to co-condensed phases. Here, using transferable coarse-grained models, we investigate the role of DNA length and concentration in shaping the stability and dynamics of HP1α-DNA condensates. We find a complex interplay between HP1α and DNA diffusion that are of different timescales at low DNA concentrations, but exhibit a non-monotonic trend and dynamic coupling with increasing DNA concentrations. Such behaviors are observed when the DNA chains are sufficiently long, explaining the experimentally characterized ability of liquid-like HP1α to trap long DNA chains into arrested domains resulting in their spatiotemporal organization. We discuss our findings in the context of DNA compaction and its influence on the relative balance between HP1α-DNA interactions and HP1α-HP1α interactions. These studies highlight the capability of physics-based molecular simulations to identify relationships between structure, dynamics, and function in the formation of chromatin condensates.