Toward Predictive Coarse-Grained Simulations of Biomolecular Condensates.

Abstract

Phase separation is a fundamental process that enables cellular organization by forming biomolecular condensates. These assemblies regulate diverse functions by creating distinct environments, influencing reaction kinetics, and facilitating processes such as genome organization, signal transduction, and RNA metabolism. Recent studies highlight the complexity of condensate properties, shaped by intrinsic molecular features and external factors such as temperature and pH. Molecular simulations serve as an effective approach to establishing a comprehensive framework for analyzing these influences, offering high-resolution insights into condensate stability, dynamics, and material properties. This review evaluates recent advancements in biomolecular condensate simulations, with a particular focus on coarse-grained 1-bead-per-amino-acid (1BPA) protein models, and emphasizes OpenABC, a tool designed to simplify and streamline condensate simulations. OpenABC supports the implementation of various coarse-grained force fields, enabling their performance evaluation. Our benchmarking identifies inconsistencies in phase behavior predictions across force fields, even though these models accurately capture single-chain statistics. This finding underscores the need for enhanced force field accuracy, achievable through enriched training data sets, many-body potentials, and advanced optimization techniques. Such refinements could significantly improve the predictive capacity of coarse-grained models, bridging molecular details with emergent condensate behaviors.