Dr. Dennis R. Livesay
Department of Bioinformatics and Genomics
University of North Carolina at Charlotte
Linking the Sensitivity within Protein Dynamics to Evolutionary Processes
Abstract: Feynman famously said nearly 50 years ago that “Everything that living things do can be understood in terms of the jigglings and wigglings of atoms.” With this in mind, the research in my lab is focused on understanding how dynamical properties vary throughout the course of divergence. Using a powerful Distance Constraint Model (DCM) we are able to quickly characterize protein structure flexibility in a robust way. The DCM, developed in close collaboration with Dr. Donald Jacobs (Department of Physics and Optical Science, UNC Charlotte), harmoniously calculates stability and flexibility profiles within proteins using an ensemble-based approach. Each microstate is represented by a network rigidity topological framework from whence flexibility and rigidity information can be derived. Based on the underlying rigidity graphs, free energies are calculated using a decomposition scheme that explicitly accounts for nonadditivity within entropy. Consequently, enthalpy-entropy compensation mechanisms are mechanistically linked through topology, and Quantitative Stability/Flexibility Relationships (QSFR) can be evaluated. Our collective results indicate that QSFR properties are highly sensitive to even the most minimal structural perturbations (i.e., point mutations). Moreover, even in stabilizing mutations that locally rigidify the protein due to improved hydrogen bonding, increased flexibility typically occurs simultaneously at remote sites to mitigate the entropic loss. Across whole protein families where sequence similarities can be as low as 25%, this sensitivity can lead to very different dynamical properties, especially in terms of the pairwise intramolecular couplings that underlie allosteric mechanisms. This work is supported by NIH GM101570.
Bio Sketch: Dr. Dennis R. Livesay received his PhD in Physical Chemistry from the University of Illinois at Urbana-Champaign in 2000, and joined the chemistry faculty at California State Polytechnic University immediately thereafter. He moved to his current position in Charlotte in 2006. Dr. Livesay has coauthored over 50 peer-reviewed research publications and is the 2010 Winner of the UNC Charlotte College of Computing and Informatics Outstanding Faculty Research Award. He is the editor of an upcoming volume in the popular Methods in Molecular Biology book series on Protein Dynamics, and is on the editorial board of a half-dozen journals, including PLoS Computational Biology, BMC Bioinformatics, and Current Protein and Peptide Science.
Refreshments will be served afterward in the PandA Café on the 1st floor of Kinard Lab.
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