Decoding the role of DNA sequence on protein-DNA co-condensation

The compaction of DNA by phase-separating, DNA-binding proteins has emerged as a key mechanism for organizing chromatin and shaping genome architecture. Although experimental studies have provided insights into the governing principles of such protein-DNA co-condensation, how DNA sequence affects this process remains unclear. Guided by experimental observations, we develop a simple polymer-based model of protein-DNA co-condensation that explicitly accounts for sequence-dependent protein binding. Using coarse-grained Brownian dynamics simulations, we demonstrate that, in the case of a homogeneous DNA, only one condensate forms in equilibrium. In sharp contrast, DNA sequence heterogeneity can result in the coexistence of multiple condensates. Interestingly, we find that interfacial DNA binding affinity controls capillary forces generated by protein-DNA condensates, offering a potential mechanism to regulate chromatin structure and 3D genome organization. To demonstrate the usefulness of our modeling framework, we compare the simulation results against published data for the condensation of DNA via Dps, Sox2, and HP1. We find that DNA sequence dictates the condensation of Sox2 and HP1 with DNA. Overall, our framework provides mechanistic insights into how DNA sequence affects protein-DNA co-condensation and paves the way for developing a deeper understanding of genome organization.