Last week, I visited Ron Zuckerman at the Molecular Foundry to talk science, meet Ron’s colleagues, and give a seminar on directions for research in molecular system-building. I learned a lot, and the seminar topic seemed to be on-target for the lab, drawing an audience that packed the seminar room.
For me, the theme of the day was peptoids and their potential for complementing biomolecules in building composite nanosystems. Ron invented peptoids while he was at Chiron almost 20 years ago, and later invented the ingenious sub-monomer approach to synthesis that makes them really interesting as a medium for molecular engineering. Peptoids deserve more attention, and I’d like to sketch why. (Ron, by the way, was the first doctoral student of the amazing Peter Schultz.)
Why do peptoids deserve more attention? Let’s start with the motivating problem: To build self-assembling molecular systems of substantial complexity will require moderately large building blocks (a few nanometers or more) that can be engineered to precisely fit other components and to fit one another. This design flexibility requires that they be modular structures, designed and made from a set of smaller parts that can be put together in a combinatorial way, with the set of possible structures growing exponentially with size like this:
N = Mn,
where M = the number of distinct kinds of parts (monomers), n = the number of monomers per structure, and N = the number of potential structures. For DNA, a typical number would be 42000; for small proteins, 2050; for small peptoids, 100030. It’s the M = ~1000 that is the special strength of peptoids: They can be built with monomers chosen from a huge range of options that offers a huge range of chemical and physical properties. Ron tells me that chain lengths up to 50 or so are now practical, so n = 30 is a conservative number.
Using the sub-monomer method, peptoid chains can be made with a sequence of any of a large portion of the commercially available amines, such as those available from Sigma Aldrich. Peptoid synthesis itself requires no protecting groups, avoiding the complexity of adding them to monomers beforehand and removing them again at each step of chain synthesis. Chain cleavage and deprotection of any reactive side-chain functional groups can be accomplished under mild conditions.
In short, peptoid synthesis is uncommonly flexible and straightforward. It’s routine enough that research groups can pick up the technique without needing a deep expertise in organic synthesis.
The peptoid community has grown over the years, recently meeting in the 6th Peptoid Summit. Ron promises a web page that will summarize the costs and virtues of peptoids to help researchers decide whether to jump in. I should mention that Molecular Foundry is an instrument-rich DOE user facility, where Ron and other staff scientists spend half their time on their own research and half collaborating on outside users’ projects.
The field has progressed beyond making only small, floppy molecules. There are now prototypes of protein-like peptoids built up from helical secondary structures loosely analogous to the alpha helices of the peptide world, and Ron showed me micrographs of large structures that self-assemble from a new peptoid motif (papers pending).
Taking a broad perspective, the structural diversity of peptoids makes them natural complements to biopolymers in building composite molecular nanosystems. They offer an approach to exploiting the molecular toolkit assembled by organic chemists and nature, using covalent bonds to lock functional parts into building blocks that can be tailored to self-assemble into larger structures. The limit today is design, not fabrication, and pushing back this limit will require a partnership that links scientific exploration to software development.
- Incorporation of Unprotected Heterocyclic Side Chains
into Peptoid Oligomers via Solid-Phase Submonomer Synthesis [pdf]