The Molecular Foundry - Biological Nanostructures - Staff

Ron Zuckermann

Facility Director, Biological Nanostructures Facility

Molecular Foundry Staff Profile

Research Interests

I am fascinated by the way nature builds precise 3-dimensional architectures. 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 inquiry 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.
- Free floating ultra-thin two-dimensional crystals from sequence-specific peptoid polymers
  The design and synthesis of protein-like polymers is a fundamental challenge in materials science. A biomimetic approach is to explore the impact of monomer sequence on non-natural polymer structure and function. We present the aqueous self-assembly of two peptoid polymers into extremely thin two-dimensional crystalline sheets directed by periodic amphiphilicity, electrostatic recognition, and aromatic interactions. Learn more
  
  Ki Tae Nam, Sarah A. Selby, Philip H. Choi, Amanda B. Marciel, Ritchie Chen, Li Tan, Tammy K. Chu, Ryan A. Mesch, Byoung-Chul Lee, Michael D. Connolly, Christian Kisielowski and Ronald Zuckermann
- Biomimetic Nanostructures: Creating a High-Affinity Zinc-Binding Site in a Folded Nonbiological Polymer
  Sequence-specific heteropolymers are growing in importance as useful tools in chemical biology, drug discovery, delivery, and materials science. Recent advances in synthetic chemistry have made it possible to generate many different types of nonnatural sequence-specific heteropolymers, providing a test of folding principles as well as potential therapeutic and diagnostic materials. Ultimately, we aim to create stable nanostructures with protein-like functions from nonnatural polymers. Learn more
  
  Byoung-Chul Lee, Tammy K. Chu, Ken A. Dill and Ronald N. Zuckermann
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.
- High-Throughput Sequencing of Peptoids and Peptide−Peptoid Hybrids by Partial Edman Degradation and Mass Spectrometry
  Oligomers of N-substituted glycines, or “peptoids”, are a new class of unnatural materials that are capable of mimicking the structure and function of peptides and proteins. A diverse array of biologically active peptoids have been discovered, including carriers for nucleic acid delivery, antimicrobials, lung surfactant mimetics, inhibitors of G-protein-coupled receptors, and ligands of both intracellular and cell surface proteins. Peptoids offer several advantages over peptides as therapeutic or diagnostic agents. Learn more
  
  - Amit Thakkar, Allison S. Cohen, Michael D. Connolly, Ronald N. Zuckermann and Dehua Pei
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

Nam, K.T.; Shelby, S.A.; Choi, P.H.; Marciel, A.B.; Chen, R.; Tan, L.; Chu, T.K.; Mesch, R.A.; Lee, B.-C.; Connolly, M.D.; Kisielowski, C.; Zuckermann, R.N., Free floating Ultra-Thin Two-Dimensional Crystals From Sequence-Specific Peptoid Polymers. In Press.

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.

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

An interview with Ron Zuckermann about his work

Research press: A Tailorable Nanotube, Formed by a Ring-shaped Protein

Research press: Nanosized Jaws Perform Like Proteins