BRD4 Biomolecular Condensates are Potential Organizers of Chromatin

Abstract

Biomolecular condensates play a central role in organizing transcriptional regulation, often forming through multivalent interactions between chromatin and associated proteins such as BRD4. While theoretical models were developed to predict that condensate stability depends primarily on condensate size, it remains unclear whether interaction behavior is determined solely by this effective size or also depends on the underlying parameters that give rise to it. In this work, we investigate condensate-mediated chromatin interactions using coarse-grained molecular dynamics simulations combined with adaptive biasing force (ABF) calculations to compute free energy profiles along a reaction coordinate defined by the separation between acetylated chromatin regions. We focus on the dissociation barrier, ΔFDissociation , which quantifies the energetic cost required to separate two merged condensates. Across a range of parameter values controlling chromatin-protein interactions, we observe that ΔFDissociation increases approximately with condensate size, consistent with theoretical expectations. However, deviations from predictions are notable. A systematic parameter sweep reveals that condensates with comparable sizes can exhibit distinct dissociation barriers, indicating that interaction behavior is not uniquely determined by size alone. Overall, this work highlights the limitations of size-based theoretical descriptions and demonstrates the importance of parameter-dependent effects in chromatin-associated condensates. Future work will extend this analysis towards constructing a phase diagram that maps merged and dissociated regimes across parameter space.