Molecular View on the Heterogeneous Structure and Dynamics of a P-Body Condensate

Abstract Biomolecular condensates are multicomponent organelles that orchestrate diverse cellular functions, yet their emergent internal structures remain poorly understood. Here we use the recently developed coarse-grained Martini3-IDP model to perform a molecular dynamics simulation of a multicomponent P-body condensate with a realistic composition, comprising six different scaffold proteins and both short and long client RNA mimics. We reveal the interior structure and dynamics of this condensate to be highly heterogeneous, featuring local solvent cavities with enhanced mobility. Furthermore, we uncover component-specific differences in conformation behavior. Whereas the terminal intrinsically disordered regions (IDRs) of Xrn1 display limited conformation sampling due to strong interactions with the scaffold proteins, the Dhh1 C-terminal IDR and Pat1 N-terminal IDR retain substantially greater flexibility. For client dynamics, length-dependent client partitioning is observed, arising from increased interaction valency of the long RNA mimic compared to the short one. For the latter, two client states were identified, characterized by distinct exchange behavior between the dilute and condensate phase. Together, this study establishes a heterogeneous picture of multicomponent condensate internal architecture and dynamics, advancing our understanding of how complex condensate architectures emerge from intricate molecular interactions in realistic condensates.