The cell nucleus is an emulsion of tiny droplets, each a distinct chemical micro-environment that controls how genes are switched on or off. This project builds a computational model to simulate these droplets—called condensates—at molecular detail for the first time. Understanding how these droplets form and behave is a fundamental gap in biology. Current experiments can observe condensates, but cannot see how their internal structure and activity change over time. This research will create a simulation that tracks every relevant molecule—chromatin, proteins, RNA—as a condensate drives gene transcription. This is fundamental science. There is no immediate practical application. But condensates are implicated in gene regulation errors that underlie many diseases, including cancers and developmental disorders. A predictive model of how they work could eventually help researchers design molecules that adjust condensate behaviour, opening a new route for treating conditions where gene expression goes wrong. For now, the goal is simply to see, for the first time, how the nucleus’s internal chemistry actually organises itself.
View original technical description
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.
Plain English summaries and category classifications on this site are generated by AI and may not perfectly reflect the original research.
Is something wrong? Let us know