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Gregory A. Weiss

Associate Professor, Chemistry School of Physical Sciences Associate Professor, Molecular Biology and Biochemistry School of Biological Sciences

PH.D., Harvard University, 1997 B.S., 1992, University of California, Berkeley

Research Interests Bioorganic chemistry, chemical biology, protein engineering, molecular biology and biochemistry

Faculty/lab web: http://www.chem.uci.edu/~gweiss/

Graduate Programs: Chemical Biology

Abstract The Weiss Laboratory pursues both chemical and biological aspects of chemical biology. Using chemistry to advance a molecular understanding of biology, the lab dissects key events in biology with exceptionally diverse combinatorial libraries as atomic-scale scalpels. Our libraries, collections of different molecules, include virus-displayed proteins and chemically or enzymatically synthesized small molecules. Libraries displayed on the surfaces of viruses also offer essentially universal molecular recognition for chemical sensors, illustrating how biology can advance chemistry. Current research in the laboratory focuses on the following three areas. 1) Multi-Dimensional Combinatorial Libraries. The collision of multiple combinatorial libraries in a single experiment opens a universe of possible combinations and experimental scenarios. For example, the Weiss laboratory reported the first library vs. library experiment. One library, displayed on the surface of a virus called a phage, included all clinical variants of the HIV protein Nef. The term allelome was coined to describe this library of all allelic variants of a single protein. The second library consisted of small molecule inhibitors of HIV Nef, synthesized by our collaborators Prof. Larry Overman and co-workers. A third source of diversity, a panel of known Nef ligands, provided a selection for functional Nef variants. Examining selectants from the allelome identified ligands preferring Nef mutations associated with rapid progression to AIDS, linking a clinically observed phenotype to an underlying molecular mechanism. The collision of inhibitor and allelomic libraries provides a method for potentially improving the effectiveness of anti-viral, anti-cancer and antibiotic treatments by anticipating and guiding avoidance of drug resistance. Ref: Olszewski, A., Weiss, G.A. (2005). Library versus library recognition and inhibition of the HIV-1 Nef allelome. J. Am. Chem. Soc. 127: 12178-12179. PDF 2) Membrane Proteins. In biology, proteins select ligands from a wide array of potential binding partners. Complementary shape and functional group arrangements dictate protein specificity and affinity. To decode determinants of protein-ligand interactions, our laboratory applies combinatorial protein libraries, which allow mutations to probe multiple sites in a protein. For example, shotgun scanning employs large protein libraries having up to 25 positions replaced with either alanine or the wild-type sidechain. Through multiple rounds of selection for binding to the ligand, enrichment is observed for wild-type sidechains in positions critical to the protein-protein binding interaction. Thus, the scalpels for our protein dissections are mutations to cutoff atoms past the beta carbons of specific amino acids. Examining the consequences of such whittling provides a vivid, panoramic portrait of the contributions to protein functionality by individual sidechains. We have demonstrated the applicability of these techniques to dissect the structure-function relationships of many different proteins. Membrane proteins, for example, represent an expanding area of interest for the lab. Their importance to biology, yet typical intractability, make membrane proteins especially attractive targets for detailed study. In addition, largely through collaborations with the laboratories of Profs. Rachel Martin and Melanie Cocco, we seek NMR structures of the targeted proteins to connect structural models with the functional consequences observed from mutagenesis. Ref: Levin, A.M., Coroneus, J., Cocco, M.J., Weiss, G.A. (2006). Exploring the interaction between the protein kinase A catalytic subunit and Caveolin-1 scaffolding domain with shotgun scanning, oligomer complementation, NMR, and docking. Prot. Science. 15: 478-486. PDF 3) The Biology-Electronics Interface. Linking biological function directly to an electronic readout represents a long-sought goal in biophysics and molecular electronics. We have demonstrated two systems directly coupling biological function with an electronic signal. The first, developed through collaboration with electrochemist Prof. Reg Penner and co-workers, features a dense phage layer covalently attached to a gold electrode. Binding to the attached phage by antigens or analytes results in a readily detectable change in impedance. Since the phage can be customized to bind most analytes, the "virus electrode" provides an inexpensive, universal biosensor. The second system, a collaboration with the physicist Prof. Phil Collins, applies carbon nanotubes incorporated into single molecule circuits. The electronics properties of proteins covalently spliced into such circuits are currently being explored. Ref: Yang, L.-M.C., Tam, P.Y., Murray, B.J., McIntire, T.M., Overstreet, C.M., Weiss, G.A., Penner, R.M. (2006). Virus electrodes for universal biodetection. Anal. Chem. 78: 3265-3270. Featured on the journal cover. PDF Ref: Goldsmith, B., Coroneus, J.G., Khalap, V.R., Kane, A.A., Weiss, G.A., Collins, P.G. (2007). Conductance-controlled point functionalization of single-walled carbon nanotubes. Science. 315, 77-81. PDF

Other Experience

Post-doctoral Fellow, Genentech, Inc., 1997—2000

Updated: Last Updated: 06/11/2009

Diaz, J.E., Howard, B.E., Neubauer, M.S., Olszewski, A., Weiss, G.A.
(2003). Exploring biochemistry and cellular biology with protein libraries.
Curr. Issues Mol. Biol. 5: 129-146. link

Weiss, G.A.*, Chamberlin, A.R.* (2003). Bridging the synthetic and biopolymer worlds with peptide-drug conjugates. Chem. Biol. 10: 201-202. Invited review.

Murase, K., Morrison, K.L., Tam, P.Y., Stafford, R.L., Jurnak, F. & Weiss, G.A. (2003). EF-Tu Binding Peptides Identified, Dissected and Affinity Optimized by Phage Display. Chem. Biol. 10: 161-168. PDF

Avrantinis, S.K., Weiss, G.A.* (2002). Chapter 14: Mapping protein functional epitopes. In Phage Display in Biotechnology and Drug Discovery, Taylor & Francis Group, LLC (Sidhu, S.S., ed.), 441-460. Invited review.

Avrantinis, S.K., Stafford, R., Tian, X. & Weiss, G.A. (2002). Dissecting the streptavidin-biotin interaction by phage-displayed shotgun scanning. ChemBioChem. 3: 1229-1234. PDF

Morrison, K.L. & Weiss, G.A. (2001). Combinatorial alanine scanning. Curr. Opin. Chem. Biol.5: 302-307.  PDF

Weiss, G.A.* (2001). Leading the way: training future chemical biologists. Chem. Innovation. 31: 3-4.