University of Minnesota
School of Physics & Astronomy

Biophysics Seminar

Thursday, March 29th 2018
10:10 am:
Biophysics Seminar in 120 PAN
Speaker: Casim Sarkar, Professor of Biomedical Engineering, University of Minnesota
Subject: Integrating experimental and computational approaches to elucidate mechanisms of binding in multivalent proteins

Multivalent proteins are ubiquitous in nature and can provide unique, exploitable properties in therapeutic applications such as increased affinity or multi-target specificity. Despite the importance of these proteins in fundamental and applied biomedical research, mechanistic quantitative descriptions of their binding kinetics are limited. We have considered such multivalent protein-protein interactions to be driven by three key variables: the binding affinity of individual monomer units, the linker length/structure between the monomers, and the overall valency of each multivalent protein. Using model synthetic proteins in which all three of these variables can be independently tuned, we have performed surface plasmon resonance experiments to quantify the kinetics of association and dissociation as a function of affinity, linker, and valency. In parallel, we developed a mechanistic model based on mass-action kinetics that explictly enumerates all possible microstates that participate in the binding reaction. Integration of these quantitative experimental and computational approaches has elucidated a number of interesting findings, including the role of valency in generating non-canonical reaction kinetics, that will be discussed. Our approach should enable better understanding of dynamic behaviors in natural multivalent proteins and lead to more rational optimization of multivalent therapeutics.

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