Ron Zuckermann

Facility Director, Biological Nanostructures
rnzuckermann@lbl.gov, 510.486.7091

Research interests
I am fascinated by the way Nature builds precise 3-dimensional architectures. But can we apply the fundamental principles we learn from protein and nucleic acid structure to man-made polymers? We have developed a new class of bio-inspired polymer called ‘peptoids’, that can be synthesized with remarkable efficiency. We have also developed custom robotic combinatorial library synthesis tools that allow us to explore vast expanses of sequence space very quickly. These technologies have opened up several new areas of exploration in my lab. For example, can we build artificial protein-like nanostructures by linking non-natural building blocks into specific sequences that spontaneously fold into defined tertiary structures? And, can we make huge numbers of sequence variations of such structures and select for sequences that have enzyme-like catalytic activity?

Current projects

Atomically-defined bio-inspired nanomaterials. Peptoids are novel class of sequence-specific oligomer based on an N-substituted glycine backbone. Hundreds of different side-chains can be easily incorporated, and oligomers of up to 50 residues can be efficiently synthesized. These oligomers can fold up into helices, and the helices can further self-assemble into compact folded single-chain structures. We explore the folding and self-assembly of peptoids coupled with new combinatorial synthesis and screening technologies to discover new nano-structured materials.

Combinatorial discovery technologies. We develop tools to allow the synthesis and screening of very large (>105 compounds) combinatorial libraries of peptide and peptoid oligomers. We are developing novel solid supports, synthesis formats, screening methods and sequencing techniques to facilitate the high-throughput screening of these libraries for novel structure and function.

Molecular recognition elements for sensor devices. Many new MEMS and NEMS sensors can be fabricated with exceptional sensitivity to detect the binding of analyte molecules. However, a critical element missing from many of these sensors are molecular recognition elements that can selectively bind particular analytes of interest. Most current sensors rely on fairly non-specific interactions like bulk poymer membranes. We aim to screen combinatorial libraries of peptoid oligomers to identify a panel of highly-specific recognition elements.

Selected publications:

Thakkar, A.; Cohen, A.S.; Connolly, M.D.; Zuckermann, R.N.; Pei, D., High-Throughput Sequencing of Peptoids and Peptide−Peptoid Hybrids by Partial Edman Degradation and Mass Spectrometry. J. Comb. Chem. 2009, 11, 294-302.

Lee, B.-C.; Chu, T.K.; Dill, K.A.; Zuckermann, R.N., Biomimetic Nanostructures: Creating a High-Affinity Zinc-Binding Site in a Folded Nonbiological Polymer. J. Am. Chem. Soc. 2008, 130, 8847-8855.

Ballister, E.R.; Lai, A.H.; Zuckermann, R.N.; Cheng, Y.; Mougous, J.D., In vitro self-assembly of tailorable nanotubes from a simple protein building block. Proc. Natl. Acad. Sci. U. S. A. 2008, 105, 3733-3738.

Chongsiriwatana, N.P.; Patch, J.A.; Czyzewski, A.M.; Dohm, M.T.; Ivankin, A.; Gidalevitz, D.; Zuckermann, R.N.; Barron, A.E., Peptoids that mimic the structure, function and mechanism of helical antimicrobial peptides. Proc. Natl. Acad. Sci. U. S. A. 2008, 105, 2794-2799.

Utku, Y.; Dehan, E.; Ouerfelli, O.; Piano, F.; Zuckermann, R.N.; Pagano, M.; Kirshenbaum, K., A peptidomimetic siRNA transfection reagent for highly effective gene silencing. Mol. BioSyst. 2006, 2, 312-317.

Lee, B.-C.; Zuckermann, R.N.; Dill, K.A., Folding a Nonbiological Polymer into a Compact Multihelical Structure. J. Am. Chem. Soc. 2005, 127, 10999-11009.

Horn, T.; Lee, B.-C.; Dill, K.A.; Zuckermann, R.N., Incorporation of Chemoselective Functionalities into Peptoids via Solid-Phase Submonomer Synthesis. Bioconj. Chem. 2004, 15, 428-435.

Burkoth, T.S.; Fafarman, A.T.; Charych, D.H.; Connolly, M.D.; Zuckermann, R.N., Incorporation of Unprotected Heterocyclic Side Chains into Peptoid Oligomers via Solid-Phase Submonomer Synthesis. J. Am. Chem. Soc. 2003, 125, 8841-8845.

Burkoth, T.S.; Beausoleil, E.; Kaur, S.; Tang, D.; Cohen, F.E.; Zuckermann, R.N., Toward the Synthesis of Artificial Proteins: The Discovery of an Amphiphilic Helical Peptoid Assembly. Chemistry & Biology 2002, 9, 647-654.

Nguyen, J.T.; Porter, M.; Amoui, M.; Miller, T.W.; Zuckermann, R.N.; Lim, W.A., Improving SH3 Domain Ligand Selectivity Using a Non-natural Scaffold. Chem. Biol. 2000, 7, 463-473.

Kirshenbaum, K.; Barron, A.E.; Goldsmith, R.A.; Armand, P.; Bradley, E.K.; Truong, K.T.V.; Dill, K.A.; Cohen, F.E.; Zuckermann, R.N., Sequence-Specific Polypeptoids: A Diverse Family of Heteropolymers with Stable Secondary Structure. Proc. Natl. Acad. Sci. U. S. A. 1998, 95, 4303-4308.

Huang, C.-Y.; Uno, T.; Murphy, J.E.; Lee, S.; Hamer, J.D.; Escobedo, J.A.; Cohen, F.E.; Radhakrishnan, R.; Dwarki, V.; Zuckermann, R.N., Lipitoids - novel cationic lipids for cellular delivery of plasmid DNA in vitro. Chem. Biol. 1998, 5, 345-354.

Figliozzi, G.M.; Goldsmith, R.; Ng, S.; Banville, S.C.; Zuckermann, R.N., Synthesis of N-(substituted)glycine Peptoid Libraries. Methods Enzymol. 1996, 267, 437-447.

Zuckermann, R.N.; Martin, E.J.; Spellmeyer, D.C.; Stauber, G.B.; Shoemaker, K.R.; Kerr, J.M.; Figliozzi, G.M.; Goff, D.A.; Siani, M.A.; Simon, R.J.; Banville, S.C.; Brown, E.G.; Wang, L.; Richter, L.S.; Moos, W.H., Discovery of Nanomolar Ligands for 7-Transmembrane G-Protein Coupled Receptors from a Diverse (N-Substituted)Glycine Peptoid Library. J. Med. Chem. 1994, 37, 2678-2685.

Zuckermann, R.N.; Kerr, J.M.; Kent, S.B.H.; Moos, W.H., Efficient Method for the Preparation of Peptoids [Oligo(N-substituted glycines)] by Submonomer Solid Phase Synthesis. J. Am. Chem. Soc. 1992, 114, 10646-10647.

Education
Ph.D. Chemistry 1989, University of California, Berkeley, CA; Thesis Advisor: Prof. Peter Schultz; "Design and synthesis of hybrid sequence-specific ribonucleases”.
B.S. Chemistry 1984, Harvey Mudd College, Claremont, CA

Past professional positions

2003 – 2005   Research Fellow, Chiron Corp.
1996 – 2003   Director of Bioorganic Chemistry, Chiron Corp.
1993 – 1996   Associate Director, Bioorganic Chemistry, Chiron Corp.
1991 – 1993   Sr. Scientist, Bioorganic Chemistry, Chiron Corp. Emeryville, CA.
1989 – 1991   Res. Scientist, New Technologies, Protos Corp. Emeryville, CA.
1984 (summer) DuPont Central Research, Wilmington, DE.
1983 (summer) Brookhaven National Lab, Upton, NY.

Links

Ron’s website: http://www.ronznet.com

http://www.lbl.gov/publicinfo/newscenter/features/08/05/05/msd-tailorable-nanotube.html

http://www.lbl.gov/publicinfo/newscenter/features/2008/MSD-nano-jaws.html