Chemically Informed Coarse-Graining of Electrostatic Forces in Charge-Rich Biomolecular Condensates
Andrés R. Tejedor, Anne Aguirre Gonzalez, Maria Julia Maristany, Pin Yu Chew, Kieran Russell, Jorge Ramı́rez, Jorge R. Espinosa, Rosana Collepardo‐Guevara
Abstract
Biomolecular condensates composed of highly charged biomolecules, such as DNA, RNA, chromatin, and nucleic-acid binding proteins, are ubiquitous in the cell nucleus. The biophysical properties of these charge-rich condensates are largely regulated by electrostatic interactions. Residue-resolution coarse-grained models that describe solvent and ions implicitly are widely used to gain mechanistic insights into the biophysical properties of condensates, offering transferability, computational efficiency, and accurate predictions for multiple systems. However, their predictive accuracy diminishes for charge-rich condensates due to the implicit treatment of solvent and ions. Here, we present Mpipi-Recharged, a residue-resolution coarse-grained model that improves the description of charge effects in biomolecular condensates containing disordered proteins, multidomain proteins, and/or disordered single-stranded RNAs. Mpipi-Recharged introduces a pair-specific asymmetric Yukawa electrostatic potential, informed by atomistic simulations. We show that this asymmetric coarse-graining of electrostatic forces captures intricate effects, such as charge blockiness, stoichiometry variations in complex coacervates, and modulation of salt concentration, without requiring explicit solvation. Mpipi-Recharged provides excellent agreement with experiments in predicting the phase behavior of highly charged condensates. Overall, Mpipi-Recharged improves the computational tools available to investigate the physicochemical mechanisms regulating biomolecular condensates, enhancing the scope of computer simulations in this field.