Title: "Integrative Approaches to Biocatalyst Discovery and Design"

Charles L. Brooks III
Cyrus Levinthal Distinguished University Professor of Chemistry and Biophysics 
Warner-Lambert/Parke-Davis Professor of Chemistry 
Professor of Chemistry and Professor of Biophysics 
Chair of Biophysics 
Departments of Chemistry and Biophysics 
University of Michigan 
 

Hosted by: Dr. Davit Potoyan

Abstract: Exploiting sequence to function relationships is fundamental to the methodology of directed evolution in the context of biocatalyst discovery and design. However, the establishment of frameworks that provide robust and reliable paths to the desired function via these approaches remains labor intensive and costly. Using an integrative approach, in which we combine the techniques of ancestral sequence reconstruction and resurrection, modeling and bioinformatics, and machine learning tools to yield structurally annotated sequence to function landscapes, we illustrate the exploration and refinement of biocatalysts directed toward stereo-specific azaphilone natural product synthesis through the enzymatic oxidative dearomatization of substrates utilizing a family of fungal-derived flavin-dependent mono-oxygenases. I will present a novel application of large-scale structure prediction through a pipeline based on AlphaFold2 together with cofactor modeling, substrate docking and machine learning to identify key residues controlling site-specific and stereo-selective asymmetric dearomatization reactions. I will discuss the pipeline we established and illustrate how we are using the structurally annotated ancestral tree to explore and inform mutational studies and prioritization of ancestral sequence resurrection for purposes of establishing a broadly substrate scoped biocatalyst in an in silico directed evolution workflow.  I will also illustrate our use of machine learning applications of variational autoencoders to visualize and systematically explore low-dimensional (latent space) representations of sequence-function relationships to elucidate the transformation between enzymes that carry-out oxidative dearomatization and those that perform decarboxylative hydroxylation. 

Bio: Professor Brooks was born in Detroit Michigan and took his early education in chemistry, physics and mathematics in rural Michigan elementary, middle and high schools. He received a Bachelor of Sciences degree from Alma College in these disciplines in 1978. While at Alma, he played football in his freshman year and midfielder on the soccer team for three years.

Remaining in the midwest, Dr Brooks pursued graduate studies at Purdue University under the direction of Professor Stephen A. Adelman. His graduate work focused on the development of non-equilibrium statistical mechanical theories for reactions on surfaces, in solids and in liquids using molecular timescale generalized Langevin equation (MTGLE) theory. In 1982 he received his Ph.D. in Physical Chemistry from Purdue University. In 2010 he was honored as Purdue University Chemistry Alumni of the year.

Postgraduate work at Harvard University with Professor Martin Karplus between the years of 1982 and 1985 focused on theoretical and computational biophysics. Dr Brooks was the recipient of an NIH Postdoctoral Fellowship between 1983 and 1985.

In 1985, Professor Brooks joined the Chemistry Faculty of Carnegie Mellon University. He rose through the academic ranks at CMU, being promoted to Professor of Chemistry in 1992. He received an Alfred P. Sloan Research Fellowship in 1992 and during this period, 1992-1993, spent a sabbatical year working at the Karolinska Institute in Stockholm, Sweden and The Scripps Research Institute in La Jolla, California. Professor Brooks moved his research group to The Scripps Research Institute in 1994. Very recently, Professor Brooks became more in touch with his roots by moving to the University of Michigan, where he holds the positions of Warner-Lambert/Parke-Davis Professor of Chemistry and Professor of Biophysics. He and his group moved to U of M in January, 2008.

Professor Brooks has received a number of honors and awards. In 1997, he was recognized for his pioneering work in computational biophysics with a Computerworld Smithsonian Award, which includes a permanent exhibit of his work in the Smithsonian Institute in Washington D.C. In 2002 he was inducted as a Fellow of the American Association for the Advancement of the Sciences. Professor Brooks was recently recognized for his impact on the field of Chemistry through his published works by being named as one of the "Top 100 Chemists of the Decade, 2000 - 2010" by Thomson Reuters. In 2012 Professor Brooks was awarded the Hans Neurath Award from The Protein Society for recent contributions of unusual merit to basic research in the field of protein science. He received the Gilda Loew Memorial Award of the International Society of Quantum Biology and Pharmacology (ISQBP) in 2014. Professor Brooks was recognized with the Morris Belkin Visiting Professorship, Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel in 2015. He was induced as a Fellow of the Biophysical Society in 2016. In 2017 Professor Brooks was named the Cyrus Levinthal Distinguished University Professor of Chemistry and Biophysics by the Unviersity of Michigan.

Professor Brooks' service to the scientific community includes several stints on review panels for the NIH and NSF, reviewing for all of the major scientific journals, as well as founding and serving on the Steering and Oversight Committees of the La Jolla Interfaces in Sciences Interdisciplinary Training Program and the Center for Theoretical Biological Physics. He directed an NIH funded research resource center for Multiscale Modeling Tools in Structural Biology (MMTSB). He is an Editorial Board Member for the journals Proteins and Molecular Simulation. Since January 2004 he has been the North American Editor for the Journal of Computational Chemistry. Professor Brooks will serve as the president of the Protein Society until 2020.

Professor Brooks has served or is serving as academic advisor to thirty undergraduate research students, thirty Ph.D. students (fourteen are currently faculty members and five are doing postdoctoral studies) and fifty-six Postdoctoral collaborators (twenty-four are currently in faculty positions). He has authored or co-authored around 432 papers, including the book Proteins: A Theoretical Perspective on Dynamics, Structure and Thermodynamics, which was a collaborative effort with M. Karplus and M. Pettitt.