Modelling physicochemical regulation of chromatin-rich nano-droplets

The internal organisation of the cell nucleus is one of the great marvels of physical chemistry. Besides housing a giant DNA-based polymer named chromatin, our nucleus is filled with thousands of proteins, RNAs, and metabolites. Transformative experiments in the past decade have proposed that chromatin and its associated biomolecules exploit the physical chemistry of phase transitions to form multi-component chromatin-rich nano-droplets inside the nucleus-termed condensates. This new paradigm conceives the nucleus as an emulsion of functionally diverse condensates: each containing a distinct chromatin region and microenvironment-a unique collection of biomolecules, metabolites, and thermodynamic parameters- to favour precise chemical reactions on the chromatin. Controlling the formation and physical properties of these condensates is hypothesised to contribute to the tight regulation of gene function in the nucleus. The question is: how?

ChromatinDroplets aims to: (1) Develop a radical computational approach to achieve the first simulation of chromatin-rich condensates with many components using molecularly accurate coarse-grained models of chromatin with deformable nucleosomes, multi-domain proteins, and RNAs. Atomistic simulations, bioinformatics, and experimental data will inform our models. (2) Use our approach to answer: How does chromatin transform the physical properties of multi-component condensates? How do condensates modulate chromatin structure? What are the parameters and mechanisms that drive chromatin condensates out of equilibrium? (3) Realise the first nonequilibrium simulation of model transcriptional condensates at sub-molecular detail, while they proceed through the stages of transcription. This alone is ground-breaking because it will reveal how the activity of condensates shapes their fundamental physical properties. This approach is new and original but solidly grounded in my earlier work.