Stephanie A. Wankowicz

Advocating for Science Research at the California Statehouse, January 2020

I am a structural and computational biologist interested in understanding how protein dynamics impact function. I am especially interested in exploring this through the lens of conformational entropy. This entropy exists within a protein’s folded state as it fluctuates between thermally accessible conformations. Proteins have likely evolved to modulate their conformational entropy to reduce the impact of conformational entropy loss during functional events such as binding or catalysis, occurring through two models: through increases in conformational entropy in spatially distant areas from the functional site or by pre-paying entropic costs through ordering in the ground state. I have created new modeling techniques to detect dynamics from X-ray crystallography and Cryo-EM structure, showing that protein conformational entropy can modulate the free binding energy by at least 1-2 kcal/mol (about the equivalent of a hydrogen bond), and my future work will focus on uncovering how conformational entropy manipulated enzyme specificity. My CV can be found here.

Enzyme specificity is pivotal to biochemical processes in living systems. While the basis for this specificity has traditionally been attributed to the static interactions between the substrate and the enzyme’s catalytic residues, the role of protein dynamics has been comparatively underappreciated. The interplay between enzyme dynamics not only affects catalysis but also introduces entropic factors during substrate recognition. However, the intricacies of entropic contributions, especially in catalysis, are often sidelined due to the inherent difficulties in their accurate modeling and quantification. My research initiative is dedicated to delineating the role of entropy in both substrate recognition and catalysis, aiming to provide a comprehensive mechanistic insight into enzymatic function. By developing novel methodologies to derive entropy values from X-ray crystallography and CryoEM data, I am poised to integrate enthalpic and entropic contributions in molecular interactions. This endeavor will revolutionize our understanding of how substrate chemistry and genetic perturbations influence the thermodynamics of substrate binding and catalysis, potentially heralding a new era in targeted ligand and protein engineering.

Currently, I am a scientist at the University of California San Francisco in James Fraser’s lab (where I also got my Ph.D.), examining the concept of conformational entropy and applying this to SARS-CoV2 drug design. This is supported by a research award from the U19 UCSF AVIDD grant and through the Chan Zuckerberg Initiative Essential Open Source Software for Science. During my Ph.D., I was supported by the Graduate Research Fellowship from the National Science Foundation, the UCSF Discovery Fellows Program, and the D.E. Shaw Award for Computational Chemistry.

Previously, I was a computational biologist in Eli Van Allen’s lab at Dana-Farber Cancer Institute/Broad Institute. My work involved understanding the relationship between tumor/germline genetics and response to therapy in genitourinary cancers using high throughput RNA, whole exome, and whole genome sequence.
Prior to that, I served as a Research Data Specialist in the Genitourinary Department at Dana-Farber Cancer Institute, overseeing clinical and translational projects for the Bladder Cancer Research Center. I hold a degree in Biochemistry and Molecular Biology from the University of Massachusetts Amherst.

Outside of science, I love running and biking around the Bay Area. On the weekends, I am frequently hiking or skiing in the Mountains.