Multiscale modelling of aberrant phase transitions in biocondensates

The spatiotemporal organization of the cell material represents one of the great wonders in physics, chemistry and biology. Compartmentalization plays a key role in such precise molecular coordination and enables cellular function.

Over the past decade, transformative experiments have revealed that most intracellular compartments are not enclosed by membranes, but instead they are dynamical assemblies, termed condensates, and thought to occur via liquid-liquid phase separation of biomolecules.

Nevertheless, the misregulation of these condensatesmostly formed by proteins and nucleic acidscan give rise to deleterious solid-like aggregates, which are associated with the proliferation of age-related and neurodegenerative disorders.In-phase aims to develop an innovative computational approach to resolve the dynamical behaviour of molecules inside functional condensates that drift their complex physicochemical behaviour into pathological solid aggregates.

To this end, we plan to develop a multiscale modelling platformcombining coarse-grained force fields and atomistic simulationswhich will address the following critical questions: What are the encoded molecular features in RNA and protein sequences regulating phase behaviour? What pushes biomolecular condensates to shift their material properties over time?

Can we prevent the proliferation of pathological aggregates induced by condensate misregulation?

The overarching goals of this project are: (1) to understand the thermodynamic and intermolecular forces driving condensates out-of-function; and (2) devise potential strategies for preventing RNA/protein aberrant phase transitions in biomolecular condensates.

This alone is ground-breaking because it will reveal the underlying mechanisms and interactions by which the structure and sequence of RNA and proteins dictate the material properties of intracellular condensates, and their implication in cellular dysfunction.