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Significance The substrate translocation through the proteasomal AAA+ motor is central to the process of protein degradation. Emerging structural studies challenge one to advance a detailed knowledge of the energetics of the translocation process. Here, we generate the relevant free energy landscape using cryogenic electron microscopy structures of the substrate-bound 26S proteasome by using a combination of coarse-grained modeling, simplified atomistic binding free energy calculations, and ATP hydrolysis energies. This landscape successfully reproduces the unidirectionality of the biological process and reveals that the unidirectional motion can be significantly enhanced/tuned by electrostatic effect. Our mutagenesis analysis identifies key residues of pore loop 1 and estimates their contribution to the translocation process. This work provides a guidance for investigating ATP-driven translocation processes of proteasomes.

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