May 6
Chemistry Department Seminar: Dr. Daniel Herschlag
The Jerry and Jean Mohrig Lecture
From Structure–function to Ensemble–function: Understanding how enzymes work
Dan Herschlag. Professor of Biochemistry. Stanford University
Understanding enzyme catalysis has been a central goal of Biochemistry for the past century, with implications spanning fundamental understanding of biology, medical interventions, and engineering enzymes to carry out challenging chemical transformations of practical value. We have largely achieved the first cornerstone of this understanding: high-confidence chemical models illustrating the roles of active site residues and cofactors for the vast majority of enzymes. Nevertheless, the second cornerstone has remained elusive: understanding and reproducing the rate enhancements of natural enzymes. To achieve this understanding, we need to advance from descriptive models of enzyme active sites to quantitative models —to extend from structure–function to ensemble–function analyses.
We have used conformational ensembles to decipher the energy landscape of serine proteases, the classic model enzymes. Using “pseudo-ensembles” built from 1231 structures of 17 serine proteases, we identified atomic-scale motions across reaction states and quantified their energetic contributions to catalysis. Our analyses reveal new catalytic features, provide an experimentally-based quantitative accounting of enzyme catalysis, and identify modular and evolvable catalytic features that may ultimately provide the elements needed to engineer new enzymes that rival those from nature. Ensemble–function analysis is a powerful widely-applicable approach that is needed to meet the current and future challenges broadly across biology, engineering and medicine.
*This seminar counts towards the chemistry major seminar attendance requirement for all majors not doing comps this year.