Protein quality control provides essential folding assistance or degradation mechanisms to prevent mechanisms to prevent deleterious off-pathway reactions of misfolding or aggregation. Bacterial caseinolytic proteases (Clp) use powerful ATPase components to unfold, translocate and degrade substrate proteins (SPs). Here, we study the unfolding and translocation of the Haloalkane Dehydrogenase (HaloTag) SP mediated by the ClpY ATPase. To probe degradation mechanisms at atomic resolution, we use an implicit solvation model (Effective Energy Function (EEF1)) and perform Langevin molecular dynamics simulations coupled with targeted molecular dynamics. The Clp machine undergoes repetitive allosteric motions that enable application of mechanical forces onto the SP by a set of central channel loops. We find that the HaloTag SP has large rotational flexibility on the surface of ClpY△ I (lacking the auxiliary I-domains), which enables force application along directions of weak mechanical resistance of the SP. Unfolding is initiated by processive removal of the outer α helices on a fast time scale, followed by slower unzipping of surface-exposed β strands.

Deciphering the mechanisms of unfolding and translocation of the halotag protein mediated by the ClpY molecular machine using computer simulations

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.