Tuesday, 03/31/2026
2:00 PM
Steinman Hall, #312
Professor William Jacobs
Princeton University, Department of Chemical and Biological Engineering
“Quantitative Prediction of Disordered Protein Partitioning and Multicomponent Phase Behavior”
ABSTRACT
Intrinsically disordered regions (IDRs) of proteins mediate sequence-specific interactions underlying diverse cellular processes, including the formation of biomolecular condensates. Although IDRs strongly influence condensate compositions, quantitative frameworks that predict and explain their phase behavior in complex mixtures remain lacking. Here we introduce a thermodynamic model that quantitatively predicts the behavior of arbitrary combinations of IDRs across a wide range of concentrations, with accuracy comparable to state-of-the-art simulations. The model learns low-dimensional, context-independent representations of IDR sequences that combine to form mixture representations, producing context-dependent interactions. These representations define a thermodynamic metric space in which distances between IDRs correspond directly to differences in their thermodynamic properties. We show that the model accurately predicts multicomponent phase diagrams in quantitative agreement with molecular simulations without explicit free-energy or phase-coexistence simulations. The resulting geometric framework provides intuitive predictions of IDR partitioning, multicomponent condensation, and context-dependent mutational effects, addressing several central problems in IDR biophysics within a single model. Systematic interrogation of the learned representations reveals how amino-acid composition and sequence patterning jointly determine mixture thermodynamics. Together, our results establish a unified and interpretable framework for predicting and understanding the behavior of complex mixtures of IDRs and other sequence-dependent biomolecules.
BRIEF ACADEMIC/EMPLOYMENT HISTORY:
William Jacobs obtained a B.S. in Physics and Engineering Science from the University of Virginia in 2010 and a Ph.D. in Theoretical Chemistry from the University of Cambridge in 2014. After completing a postdoc in Theoretical Chemistry and Biophysics at Harvard University, he began his independent career at Princeton University in 2019, where he is also affiliated with the department of Chemical and Biological Engineering, the Princeton Materials Institute, and the Biophysics program.
MOST RECENT RESEARCH INTERESTS:
Statistical mechanics, soft matter, biophysics
