Protein aging dynamics: A perspective from non-equilibrium coarse-grained models

Abstract The aging of biomolecular condensates has been implicated in the pathogenesis of various neurodegenerative diseases, characterized by a transition from a physiologically liquid-like state to a pathologically ordered structure. However, the mechanisms governing the formation of these pathological aggregates remain poorly understood. To address this, the present study utilizes coarse-grained molecular dynamics simulations based on Langevin dynamics to explore the structural, dynamical, and material property changes of protein condensates during the aging process. Here, we further develop a non-equilibrium simulation algorithm that not only captures the characteristics of time-dependent amount of aging beads but also reflects the structural information of chain-like connections between aging beads. Our findings reveal that aging induces compaction of the condensates, accompanied by a decrease in diffusion rates and an increase in viscosity. Further analysis suggests that the heterogeneous diffusivity within the condensates may drive the aging process to initiate preferentially at the condensate surface. Our simulation results align with the experimental phenomena and provide a clear physical picture of the aging dynamics.