The Faculty



University of Illinois at Urbana/Champaign B.S. 1998-2002

University fo California Berkeley Ph.D. 2002-2007

California Institute of Technology Postdoc. 2007-2010

Research Overview

compounds of amazing complexity for biological, medical, and materials research, but the efficiency by which molecules are prepared, and thus the speed at which they are applied toward societal problems, is limited by a number of factors.  Of these, extended synthetic sequences, isolation of intermediates, wasteful protection and deprotection steps, and low catalyst activity are particularly notable.  Research in the Lewis group focuses on identifying solutions to these problems through the development of new catalysts for a variety of key chemical transformations.   We are particularly interested in systems that can ultimately be integrated into biological systems (e.g. living cells) to augment the biosynthetic capability of life. Projects relevant to the Biophysics program at the University of Chicago include structure guided and directed evolution of natural enzymes and artificial metalloenzymes and structure-activity relationships on these engineered systems. 

Developing these new catalyst systems requires a dynamic and highly interdisciplinary research environment and is well suited for the collaborative nature of the Biophysics program. There are opportunities for rigorous training in organic and organometallic synthesis, protein engineering and evolution, molecular biology, structural and biophysical characterization of proteins, X-ray crystallography, molecular dynamics simulations, and computational modeling. Students are encouraged to exploit all of these tools in collaboration with other members of the Biophysics program to develop new catalysts for fundamentally important chemical transformations.

Project areas of interest for Biophysical Sciences students

1) Protein Engineering and Directed Evolution. Enzymes are increasingly employed for chemical synthesis due to their high catalytic efficiency, high regio- and stereoselectivity, and extremely mild operating conditions.  Perhaps the most attractive feature of these catalysts however, is their ability to be systematically optimized for a particular application using directed evolution.  Thus, while the activity of a given enzyme may or may not be particularly general (with respect to substrate scope for example), this activity is highly generalizable such that activity toward a desired substrate can be rapidly improved using successive rounds of mutagenesis and screening.  We are exploiting this property to engineer various halogenases for use in organic synthesis due to the importance of halogenated compounds as both building blocks and pharmaceuticals.  We are using structure-guided and directed evolution schemes to expand the substrate scope and improve the practicality of these valuable catalysts. We then explore structure function relationships in improved enzymes to help rationalize mechanisms for the observed improvements and to inform subsequent engineering efforts. Several other enzymatic solutions for new C-H bond hetero-functionalization reactions are also being pursued.
2) Artificial Metalloenzymes. Many powerful reactions, particularly those catalyzed by non-biological metals, are not found in nature, so systems that combine the reactivity of metal catalysts with the evolvability and specificity of enzymes are highly sought after. To expand the scope of reactions are developing new classes of artificial metalloenzymes (ArMs), hybrid constructs comprised of protein scaffolds and metal catalysts.  Optimization of ArMs using directed evolution is being used to produce highly active enzymes for in vitro and in vivo transition metal catalysis.  We are focusing on incorporating privileged transition metal catalysts into protein scaffolds to generate bioorthogonal variants of known reactions.  This is illustrated by our recent work on dirhodium tetracarboxylate and manganese terpyridine ArMs. We then hope to demonstrate that scaffolds can be used to augment the reactivity of metal catalysts in order to access new reactions not possible in the absence of the scaffold protein. Our most recent work is beginning to explore new ways that protein structure and dynamics can, in fact, alter metal reactivity. Ultimately, these enzymes will be utilized in metabolic engineering efforts for the biosynthesis of natural product derivatives and even completely synthetic compounds.  Such an approach would greatly facilitate the synthesis of complex molecules and enable exciting collaborations to explore the biological activity of these compounds.