Biophysical theory for condensate dynamics: advancing beyond minimal models

About This Grant

Project Summary/Abstract Cells host non-membrane-bound organelles, many of which form through a phase-separation mechanism. These dense assemblies of proteins and nucleic acids, termed biomolecular condensates, enable key cellular functions from ribosomal assembly to stress response and metabolism, and are implicated in neurodegenerative diseases and cancers. In contrast to membrane-bound organelles, which are impermeable to most cellular molecules, biomolecular condensates are open to their surrounding environment. They constantly exchange components with the dilute phase and can form and dissolve as needed in response to cellular signals. Such dynamical exchanges are crucial to the biochemical processes taking place inside condensates and to the response of condensates to a changing environment, as well as to the regulation of the number, size, and placement of condensates in the cell. A quantitative understanding of condensate dynamics is therefore key to discovering the physical principles and biological mechanisms underlying condensate functions. Advances in imaging techniques have led to great improvements in the measurement of dynamical properties of condensates, and increasingly allow for the probing of condensates with multiple components and complex structures in an intact cellular environment. However, there is a very limited set of mathematical models aimed at quantitatively interpreting these experimental results. The growing wealth of quantitative data calls for a new generation of dynamical models capable of capturing the complexities encoded in the data. We propose to develop biophysical models to unravel both the physical principles and biological mechanisms underlying condensate dynamics via interpreting highly quantitative data, such as from single-molecule tracking. We will investigate condensate dynamics by integrating biophysical modeling, coarse-grained simulations, machine learning, and targeted experiments with expert collaborators – a research style characteristic of our lab. Specifically, we expect this research program to (1) provide a quantitative picture of the key factors controlling how long a molecule dwells within a condensate, (2) predict the timescales of material exchange for multi-component, multi-state condensates, and (3) bring new insights into the molecular interaction network and its relationship to spatial and dynamic heterogeneity within condensates. Beyond these immediate research goals, we will address broader questions in the long term, including: How are the internal structure and dynamics of multi-species condensates related? How does the complex intracellular environment impact condensate dynamics? And how do the dynamics of condensate components influence their biological functions? Ultimately, the results and tools developed in this research will advance our understanding of the dynamic behaviors of biomolecular condensates, shedding light on their functions in health and disease, and paving the way for condensate bioengineering.