Speaker
Description
Cellular processes are organized by the phase separation of proteins into biomolecular condensates. These condensates are regulated by post-translational modifications, most notably phosphorylation. Phosphorylation of proteins is catalysed by kinases which consumes the chemical fuel ATP. While the phosphorylation of TDP-43 is closely linked to neurodegenerative disease, how TDP-43 is phosphorylated remains poorly understood. It is not clear whether kinases interact directly with condensates or primarily with TDP-43 proteins within the dilute phase. Molecular dynamics simulations can potentially resolve these interactions, yet modelling fuel-driven, non-equilibrium dynamics remains a significant computational challenge. We show how to simulate chemical-driven enzymatic phosphorylation of proteins in coarse-grained molecular dynamics. Importantly, we demonstrate how to validate the thermodynamic consistency of these simulations by automatically constructing Markov-state models from the resulting trajectories. Our results reveal that the kinase Casein kinase 1 delta binds preferentially to TDP-43 condensates over the dilute phase, thereby accelerating phosphorylation. While enzymes initially localise to the droplet surface, phosphorylation enables enzymes to interact with the condensate interior. Our simulations demonstrate that ultimately this localised enzymatic activity can trigger the complete dissolution of TDP-43 condensates.