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Prediction of the Translocation Kinetics of a Protein from Its Mechanical Properties

Daniel K. West ^* , David J. Brockwell  and Emanuele Paci ^*

^* School of Physics and Astronomy, and Institute of Molecular and Cellular Biology, University of Leeds, Leeds LS2 9JT, United Kingdom

Correspondence: Address reprint requests and inquiries to E. Paci, E-mail: e.paci{at}leeds.ac.uk.

Proteins are actively unfolded to pass through narrow channels in macromolecular complexes that catalyze protein translocation and degradation. Catalyzed unfolding shares many features that characterize the mechanical unfolding of proteins using the atomic force microscope (AFM). However, simulations of unfolding induced by the AFM and when a protein is translocated through a pore suggest that each process occurs by distinct pathways. The link, if any, between each type of unfolding, therefore, is not known. We show that the mechanical unfolding energy landscape of a protein, obtained using an atomistic molecular model, can be used to predict both the relative mechanical strength of proteins when unfolded using the AFM and when unfolded by translocation into a pore. We thus link the two processes and show that the import rate through a pore not only depends on the location of the initiation tag but also on the mechanical properties of the protein when averaged over all the possible geometries that are relevant for a given translocation initiation site.