Nonequilibrium chemomechanical transduction of ATP-driven protein unfolding in the 26S proteasome

Abstract AAA+ ATPases are essential ATP-driven molecular machines with diverse cellular functions, including protein unfolding, active transport, and chromatin remodeling. Despite their broad importance, the precise mechanisms by which energy transduction drives protein unfolding in AAA-ATPase motors remain unclear. Here, we present a probabilistic model that simulates nonequilibrium chemomechanical transduction of ring-like AAA-ATPase motors during substrate unfolding in the 26S proteasome. By capturing the sequential cycling of ATP hydrolysis around the ATPase ring, our model explores a wider range of coordinated conformational transitions than previously observed experimentally. Our simulations reveal multiple high-probability pathways for state transition during hand-over-hand translocation of substrate, elucidating the nonequilibrium dynamics of around-the-ring energy transduction in AAA-ATPase motors. These findings, extensively examined by experiments, provide quantitative insights into chemomechanical coupling that are likely conserved across the AAA+ protease or unfoldase superfamily. This work offers a theoretical framework for understanding ring-like AAA+ translocation motors in general.