Simulating the directional translocation of a substrate by the AAA+ motor in the 26S proteasome

Abstract

This work explored the molecular origin of substrate translocation by the AAA+ motor of the 26S proteasome. This exploration was performed by combining different simulation approaches including calculations of binding free energies, coarse-grained simulations, and considerations of the ATP hydrolysis energy. The simulations were used to construct the free energy landscape for the translocation process. This included the evaluation of the conformational barriers in different translocation steps. Our simulation reveals that the substrate translocation by the AAA+ motor is guided in part by electrostatic interactions. We also validated the experimental observation that bulkier residues in pore loop 1 are responsible for substrate translocation. However, our calculation also reveals that the lysine residues prior to the bulkier residues (conserved along pore loop 1) are also important for the translocation process. We believe that this computational study can help in guiding the ongoing research of the proteasome.