(347a) Computational Characterization of Effects of Mutations on the Allosteric Communication Pathways of Hsp70

Authors: 
Ortiz, V., Columbia University
Ribeiro, A. A. S. T., Columbia University

Proteins from the Hsp70 chaperone family are essential in the survival of cells under stress, and also serve a general housekeeping role in maintaining protein homeostasis by helping mis-folded or denatured proteins fold properly. Hsp70s are over-expressed in tumor cells, and are associated with helping in their survival. They are also linked to neurological disorders such as Alzheimer’s, Parkinson’s and Huntington’s diseases. In particular, inhibitors of Hsp70 have shown efficacy for the treatment of cancer and Alzheimer’s disease. The functional cycle of Hsp70 is under allosteric control. Allostery is the mechanism by which a stimulus event triggers a signal that propagates through the molecule, and causes a response in another region of the molecule. Here, we apply computational tools to characterize allostery in Hsp70, to gain a better understanding of how signals propagate in this molecule, and to better predict the effects of drugs in its function. We use energy-based network analysis methods recently developed in our group, to predict the effects of residue mutations on the efficiency of allosteric signal propagation of Hsp70. We studied the wild type and mutants D388R, T11V, K70E and D393R, and found that experimentally measured allosteric activity correlates well with our calculations of energetic coupling between different domains in the protein. The ability to predict the effects of perturbations, such as mutations, on the ability of Hsp70 to propagate signals will help us in our search for allosteric drugs that can provide both Hsp70 inhibition/activation and high selectivity at the same time.