Folding Sequence-Defined Peptoid Polymers into Protein Mimetic Nanostructures

• Dr. Ronald Zuckermann, Biological Nanostructures Facility, The Molecular Foundry, Lawrence Berkeley National Laboratory
• Sponsored by the Golden Gate Polymer Forum
• 6:30-7:30pm, Online via Zoom, $5 donation/Free, Registration required (registration deadline is Sept. 28th at 1pm)

Abstract:

A longstanding challenge in molecular biomimicry is to build synthetic nanostructures with the same architectural sophistication as proteins. One of the most promising ways to do this is to synthesize sequence-defined, non-natural polymer chains that, like in nature, spontaneously fold and assemble into precise three-dimensional structures. This was originally a synthesis problem, but the automated solid-phase submonomer synthesis method now allows one to efficiently synthesize high-purity, sequence-defined peptoid polymers up to 50 monomers in length. The method uses readily available primary amine synthons, allowing hundreds of chemically diverse side chains to be cheaply introduced.

This remarkable synthetic capability raised the next problem: which chemical sequences in a chain encode for precise folding into a 3D structure? This is essentially the protein folding problem extended to the non-natural world. Using results from our synthetic capabilities in concert with computational modeling and high-resolution characterization techniques, we will discuss the design, synthesis, assembly, and engineering of a variety of protein-mimetic nanostructures. We show by direct cryo-TEM imaging, AFM, NMR, and x-ray scattering, that all known crystalline peptoid assemblies share a universal secondary structure motif, the cis-Sigma strand, based on a backbone fold containing all cis-amide bonds. The unexpected universality of peptoid backbone folding offers a unique opportunity to rationally design and engineer these materials to create robust nanomaterials capable of protein-like functions, such as specific molecular recognition and catalysis.

Bio:

Ronald Zuckermann is a Sr. Research Advisor at the Molecular Foundry at the Lawrence Berkeley National Laboratory, where he studies the mimicry of biological architectures using bio-inspired polymers. He received his BS in Chemistry in 1984 from Harvey Mudd College where he did undergraduate research in synthetic organic chemistry. He then went on to UC Berkeley to study Bioorganic Chemistry with Prof. Peter Schultz. His thesis work was on the synthesis of semi-synthetic nucleases capable of the sequence-specific cleavage of RNA. After receiving the first Schultz group PhD in 1989, he became one of the founding chemists at Protos Corp., a combinatorial drug discovery start-up in Emeryville, CA. There he helped develop several key drug discovery technologies such as robotic combinatorial library synthesizers, affinity selection methods, and a novel class of heteropolymers called “Peptoids”. Chiron Corp. acquired Protos in 1991 where this work continued and was applied to small molecule drug discovery, new biomaterials, and nucleic acid delivery. Dr. Zuckermann was promoted to Research Fellow in 2003. In early 2006, he left Chiron to direct the Biological Nanostructures Facility of the Molecular Foundry at Lawrence Berkeley National Laboratory to do research at the interface of chemistry, biology and nanoscience. There he pioneered the field of peptoid nanostructure, folding sequence-defined peptoid polymer chains into protein-like nanoarchitectures. He has published over 180 papers and is co-inventor on 38 patents.