Mpipi-P: A Coarse-Grained Model for Simulating Phosphorylation Reactions in Biomolecular Condensates

Abstract

The formation, dynamics, composition, and dissolution of biomolecular condensates are often regulated by post-translational modifications such as phosphorylation. Here, I introduce Mpipi-P, a coarse-grained model for simulating phosphorylated proteins and phosphorylation reactions in biomolecular condensates. Mpipi-P is the first coarse-grained model to enable explicit representation of phosphorylation reactions and to capture the kinetics of these reactions. Mpipi-P is able to correctly predict the sequence-specific effects of phosphorylation on biomolecular condensate formation and can demonstrate that phosphorylation inhibits FUS condensate formation in a dose-dependent manner. Additionally, Mpipi-P is used to show that FUS phosphorylation can contribute to but is unlikely to be the primary driver of DNA damage repair-associated condensate dissolution. These findings demonstrate that Mpipi-P can provide mechanistic insight into how phosphorylation modulates biomolecular condensates. The Mpipi-P reaction framework can be extended to study other phosphorylation-regulated condensates and, more broadly, enzymatically active condensates in general.