(59e) A Scalable Coarse-Grained Chromatin Model with Specific Molecular Recognition

Chromatin’s three-dimensional structure is central to gene regulation, and its deregulation can lead to diseases such as cancer. Although experimental techniques like Hi-C, ChIA-PET, 3D-FISH, and ChromEMT have provided crucial insights into chromatin organization, they struggle to capture real-time dynamics. As a result, computational simulations are increasingly indispensable for understanding how chromatin’s structural rearrangements and temporal evolution affect gene expression.

Existing ultra-coarse-grained (UCG) models often excel at capturing large-scale chromatin organization but may overlook key local events, such as transcription factor binding or histone modifications, due to resolution limits. Conversely, high-resolution models can accurately depict these finer details but are computationally prohibitive on genome-wide scales. To address this challenge, we have developed a complete UCG model featuring a novel “lock-and-key” (LnK) potential. By assigning specific binding sites to coarse-grained particles, the LnK approach replicates biologically meaningful histone-histone and histone-DNA interactions while maintaining efficiency at larger scales.

We demonstrate the capabilities of our model through two case studies: (1) spontaneous self-assembly of histones into a functional and stable octamer, and (2) DNA wrapping around a pre-assembled octamer. These examples highlight how the LnK-based framework can capture both high-level chromatin architecture and essential local molecular interactions. The same setup can incorporate additional components—such as dCas9 or chemical epigenetic modifiers.
Looking ahead, we will extend our system to million-base-pair domains, enabling the simultaneous examination of chromosome-scale organization and single-nucleosome interactions. This integrated approach provides a more comprehensive understanding of multi-scale chromatin processes, offering valuable insights into gene regulation, disease mechanisms, and potential avenues for therapeutic intervention.