Computational Modeling of Protein Degradation by Biological Nanomachines

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Cell survival is critically dependent on tightly regulated protein degradation mechanisms. Biological nanomachines that mediate protein degradation use repetitive mechanical forces to unfold, translocate (move), and destroy excess or defective proteins. Understanding these mechanisms is of central importance for deciphering the details of essential cellular processes. This project will use computer simulations at multiple scales to elucidate 1) the dependence of protein unfolding and translocation actions on force directionality and 2) the nature of collaboration between components of the biological machines involved in the degradation process. The knowledge gained through this project will advance understanding of the relationship between structure and function in these biological nanomachines and will reveal fundamental principles of protein unfolding and translocation. This project integrates the training of undergraduate and graduate students in computational biophysical chemistry through addressing advanced scientific problems. Increased participation of underrepresented minorities in computational sciences will be promoted through educational and mentoring efforts. This goal will be achieved through the collaboration between the University of Cincinnati and Central State University (CSU), a Historically Black College and University, and will combine outreach activities at CSU with research experience opportunities for underrepresented minorities in the PI's laboratory. The results of this project will be disseminated widely to the general public by the PI, graduate and undergraduate students through publications, conference presentations, the web, and seminars at CSU.This project will elucidate the effect of mechanical anisotropy on unfolding and translocation of multidomain substrate proteins by bacterial Clp ATPases, which are members of the AAA+ superfamily of biological nanomachines. Multiscale models will be developed to probe nanomachine-mediated threading of multidomain constructs of substrate proteins with diverse topology and mechanical stability along specific directions. Computer simulations using these models will be complemented by experiments conducted by collaborators to pinpoint remodeling pathways in restricted and unrestricted geometries. The project will also elucidate the collaboration between Clp ATPase and peptidase components for protein threading. Computer simulations of atomistic and coarse-grained models will be performed to obtain a detailed understanding of allosteric conformational transitions of the peptidase and their role in substrate translocation. These simulations, in conjunction with experimental studies conducted by collaborators, will establish the residue-level interactions that underlie component specialization in these biological machines.