2021 New Investigator Grant
Joshua Lequieu, Ph.D. Assistant Professor, Chemical and Biological Engineering, Drexel University
Unraveling multicomponent biomolecular condensates with field-theoretic simulations
Abstract
In the past decade, a new class of intracellular compartment has been discovered which has upended the canonical picture of cellular organization. These new compartments, known collectively as biomolecular condensates, differ from typical compartments because they do not rely on membranes to physically wall off different regions of the cell. Instead, condensates form due to a process known as phase separation, the same phenomenon that causes the coalescence of oil droplets in water. The realization that cells can utilize phase separation to organize their interior has led to a fundamental shift in cell biology and has pro-vided new paradigms for understanding and treating disease. While the rules that govern phase separation are well-established (i.e. thermodynamics), biomolecular condensates remain poorly understood largely because they are complex mixtures containing hundreds of different protein and nucleic acid molecules. In this proposal, we develop a novel theoretical framework that can explain how this complicated web of molecular interactions gives rise to phase-separated condensates with precisely controlled compositions. The key to our approach is field-theoretic simulations, a powerful technique that can predict the phase separation of biomolecular mixtures from protein/nucleic acid sequence alone. Due to their advantageous mathematical structure, field-theoretic simulations are thousands of times faster than comparable techniques and can examine complex biomolecular condensates that are inaccessible with current methods. After validating our approach using hundreds of experimental measurements, we will interrogate the rich multicomponent interactions that drive condensate formation and will quantify how an archetypal condensate controls its composition. Taken together, our approach will provide an unprecedented look into the molecular interactions that govern the formation and function of biomolecular condensates and is anticipated to reveal new insights into these fascinating subcellular structures.