CAREER: Programmable control of biomolecular condensate self-assembly

Princeton University, Princeton NJ

Investigators

Abstract

NONTECHNICAL SUMMARY The cytoplasm within a living cell consists of thousands of different types of molecules, including proteins and nucleic acids such as RNA. In order for many biological functions to occur, this complex mixture must be organized, with specific types of biomolecules either colocalizing or assembling into larger structures. This spatial organization is often dynamic, in the sense that many structures assemble, disassemble, or rearrange themselves in response to external stimuli. This CAREER award focuses on a particular class of structures known as biomolecular condensates, which are liquid-like structures composed of proteins and RNA. Using theoretical models and computer simulations, the PI aims to understand the mechanisms by which biomolecular condensates assemble and interface with one another, as well as how these processes can be controlled. These theories will not only improve our understanding of how biomolecules are organized inside of living cells, but also help to guide the development of biomimetic "living materials" that can similarly respond dynamically to specific stimuli. This project includes an integrated education plan that will train future scientists working at the interface of computational materials research and theoretical biophysics. This plan is motivated by the need to teach aspiring theorists both fundamental concepts and state-of-the-art methods for performing practical calculations. To unify the presentation of these topics, the PI will develop a pair of graduate-level courses that cover modern theories of complex fluids in parallel with related computer simulation techniques. These courses will emphasize applications relevant to the research activities of this award, as well as to current research at the interface of biology and soft condensed matter physics more broadly. TECHNICAL SUMMARY This CAREER award supports theoretical and computational research to elucidate the self-assembly dynamics of intracellular biomolecular condensates, a recently discovered class of liquid-like protein and RNA-rich structures. Although many condensates assemble spontaneously, the dynamics of these intracellular self-assembly processes appear to be tightly controlled both spatially and temporally. This project will establish the physical principles underlying the assembly dynamics of multicomponent condensates by probing the mechanisms that allow condensates to assemble rapidly and in response to specific stimuli. Building on recent advances in the theory of multicomponent phase behavior, this research will use coarse-grained molecular simulations and rare-event sampling techniques to: 1) derive design rules for selectively seeding the assembly of one condensate out of a large number of competing structures, 2) investigate the relationship between the structure of protein/RNA interaction networks and the emergent condensate morphology, and 3) develop a molecular-level theory to describe how chemical reactions affect the nucleation dynamics of self-assembled condensates. The results of these studies will be used to guide future experimental efforts to manipulate biomolecular condensates in vivo, construct synthetic biomimetic condensates, and engineer stimulus-responsive soft materials. The integrated education plan addresses the need to unify the presentation of theoretical concepts, molecular-scale simulations, and continuum-level numerical methods in modern graduate-level coursework. The PI will develop a pair of graduate-level courses that cover topics from equilibrium and non-equilibrium statistical mechanics in parallel with techniques for performing practical calculations. The first of these courses will introduce students to modern molecular-level theories of complex fluids and non-equilibrium systems alongside closely related computational tools. The second course will cover the kinetics of phase transformations, with a focus on numerical methods spanning both molecular simulation and continuum-level approaches. Both courses will emphasize applications relevant to current research at the interface of biology and soft condensed matter physics by incorporating case studies from the current literature. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.