Stephanie Wankowicz
Structural Mechanisms of Conformational Entropy
Ligand specificity is foundational to the biochemistry of living organisms. However, our atomistic understanding of enzyme specificity is driven primarily by static interactions between a substrate and catalytic residues, ignoring the critical component of protein dynamics. The influence of dynamics is frequently underestimated because of the complexities in modeling multiple states and quantifying entropy. Our overall goal is to elucidate the role of entropy in substrate specificity and catalysis, aiming to provide a more comprehensive thermodynamic understanding of enzyme function.
We attack this problem by detecting and modeling protein dynamics in X-ray crystallography and single-particle cryo-EM data. X-ray crystallography and cryo-EM studies collect data averaged over tens of thousands to billions of individual system copies. Each molecule within the system can adopt a different conformation (conformational heterogeneity) and may differ slightly in chemical composition (compositional heterogeneity). We leverage optimization algorithms and generative AI to improve the modeling of conformational and compositional heterogeneity in X-ray crystallography and cryo-EM data. We combine this modeling strategy with machine learning and biophysical measurements to determine how entropy influences binding specificity and catalysis.
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