eBriefing

Structural Creativity: Foldamers and their Uses in Chemical Biology

Structural Creativity
Reported by
Sarah Webb

Posted July 20, 2007

Overview

As we have extended our understanding of structure and function in natural peptides, researchers have branched out to examine foldamers, non-natural polymers that fold into a compact structure. By moving sidechains, adding atoms and functional groups within the fundamental amino acid structure, researchers can design entirely new molecules.

At the April 12, 2007, meeting at the Academy, speakers presented research in the growing field of biomimetic polymers. Bill DeGrado of the University of Pennsylvania discussed his group's work to understand the recognition of transmembrane proteins. Daniel Appella of the NIDDK spoke about a variety of non-natural biomimetic polymers: β-peptides containing cyclohexane and cyclopentane moieties; peptide nucleic acids (PNA); and peptoids, non-chiral polymers with a sidechain extending from the amide nitrogen of the amino acid. James Petersson, a postdoctoral researcher at Yale University, described the design, synthesis, and characterization of protein-like structures composed of β-peptides.

Web Sites

Bill DeGrado's Research Group
Bill DeGrado's group at the University of Pennsylvania designs proteins and small molecules to understand the structure and function of macromolecules.

Daniel Appella's Web site
Additional information on Appella's efforts to design and synthesize molecules with biological activity.

Schepartz Laboratory of Chemical Biology
The Schepartz group at Yale University uses chemical tools to study cellular protein–protein and protein-DNA interactions.

The Gellman Group
More information about potential foldamer applications, including functions in protein–protein interactions and design of β-sheets. Don't miss Samuel Gellman's manifesto (PDF, 159 KB), and you can also see this PowerPoint workshop (PDF, 3.1 MB).


Books

Hecht S, Huc I, eds. [forthcoming 2007]. Foldamers: Structure, Properties, and Applications. Wiley-VCH, Hoboken, NJ.
Amazon


Journal Articles

Design of Foldamers That Act on and in Membranes

Ivanov I, Vemparala S, Pophristic V, et al, 2006. Characterization of nonbiological antimicrobial polymers in aqueous solution and at water-lipid interfaces from all-atom molecular dynamics. J. Am. Chem. Soc. 128: 1778-1779.

Kuroda K, DeGrado WF. 2005. Amphiphilic polymethacrylate derivatives as antimicrobial agents. J. Am. Chem. Soc. 127: 4128-4129.

Li W, Metcalf DG, Gorelik R, et al. 2005. A push-pull mechanism for regulating integrin function. Proc. Natl. Acad. Sci. USA 102: 1424-1429. Full Text

Litvinov RI, Vilaire G, Li W, et al. 2006. Activation of individual αIIbβ3 integrin molecules by disruption of transmembrane domain interactions in the absence of clustering. Biochemistry 45: 4957-4964.

Yin H, Litvinov RI, Vilaire G, et al, 2006. Activation of platelet αIIbβ3 by an exogenous peptide corresponding to the transmembrane domain of αIIb. J. Biol. Chem. 281: 36732-36741. Full Text

Yin H, Slusky JS, Berger BW, et al. 2007. Computational design of peptides that target transmembrane helices. Science 315: 1817-1822.

Backbone Substitutions to Control the Folding of Peptide Nucleic Acids and Peptoids

Appella DH, Christianson LA, Karle IL, et al. 1996. β-peptide foldamers: robust helix formation in a new family of β-amino acid oligomers. J. Am. Chem. Soc. 118: 13071-13072.

Englund EA, Appella DH. 2007. γ-substituted peptide nucleic acids constructed from L-lysine are a versatile scaffold for multifunctional display. Angew. Chem. Int. Ed. Engl. 46: 1414-1418.

Englund EA, Appella DH. 2005. Synthesis of γ-substituted peptide nucleic acids: a new place to attach fluorophores without affecting DNA binding. Org. Lett. 7: 3465-3467.

Englund EA, Xu Q, Witschi MA, Appella DH. 2006. PNA–DNA duplexes, triplexes, and quadruplexes are stabilized with trans-cyclopentane units. J. Am. Chem. Soc. 128: 16456-16457.

Hara T, Durell SR, Myers MC, Appella DH. 2006. Probing the structural requirements of peptoids that inhibit HDM2-p53 interactions. J. Am. Chem. Soc. 128: 1995-2004.

Lawton GR, Appella DH. 2004. Nonionic side chains modulate the affinity and specificity of binding between functionalized polyamines and structured RNA. J. Am. Chem. Soc. 126: 12762-12763.

Myers MC, Wang J-L, Iera JA, et al. 2005. A new family of small molecules to probe the reactivation of mutant p53. J. Am. Chem. Soc. 127: 6152-6153.

β-amino Acid Proteins: Design, Synthesis, and Comparison to Natural Proteins

Daniels DS, Petersson EJ, Qiu JX, Schepartz A. 2007. High-resolution structure of a β-peptide bundle. J. Am. Chem. Soc. 129: 1532-1533.

Horne WS, Price JL, Keck JL, Gellman SH. 2007. Helix bundle quaternary structure from αβ-peptide foldamers. J. Am. Chem. Soc. 129: 4178-4180.

Petersson EJ, Craig CJ, Daniels DS, et al. 2007. Biophysical characterization of a β-peptide bundle: comparison to natural proteins. J. Am. Chem. Soc. 129: 5344-5345.

Qiu, JX, Petersson EJ, Matthews EE, Schepartz A. 2006. Toward β-amino acid proteins: a cooperatively folded β-peptide quaternary structure. J. Am. Chem. Soc. 128: 11338-11339.

Speakers

William F. DeGrado, PhD

University of Pennsylvania
e-mail | web site | publications

William (Bill) DeGrado has been a professor in the Department of Biochemistry and Biophysics at the University of Pennsylvania since 1996. Prior to moving to UPenn, he worked for 15 years at Dupont, with a final position of senior director in medicinal chemistry. DeGrado earned his PhD in organic chemistry from the University of Chicago in 1981. He is a member of the National Academy of Sciences and a fellow of the American Academy of Arts and Sciences and the American Association for the Advancement of Science. In 2003 DeGrado received the Merrifield Award from the American Peptide Society for career achievement in peptide research.

Daniel H. Appella, PhD

National Institute for Diabetes & Digestive & Kidney Diseases (NIDDK)
e-mail | web site | publications

Daniel Appella is an investigator in the Laboratory of Bioorganic Chemistry in the NIH's National Institute for Diabetes & Digestive & Kidney Diseases (NIDDK). Prior to moving to NIH, he was an assistant professor of chemistry at Northwestern University. He completed graduate work with Samuel Gellman at the University of Wisconsin-Madison, completing his PhD in 1998. Appella was an NIH postdoctoral fellow in the laboratory of Stephen Buchwald at Massachusetts Institute of Technology from 1998–2001. He has received both a Beckman Young Investigator Award and a Presidential Early Career Award for Scientists and Engineers.

E. James Petersson, PhD

Yale University
e-mail | web site | publications

James Petersson is an NIH postdoctoral fellow in the laboratory of Alanna Schepartz at Yale University. He earned his undergraduate degree in chemistry from Dartmouth College in 1998. He completed his PhD in 2005, working with Dennis Dougherty at California Institute of Technology, where he received the McCoy award for outstanding graduate research in chemistry. He also received an NIH predoctoral fellowship.


Sarah Webb

Before hanging up her labcoat, Sarah Webb earned a PhD in bioorganic chemistry from Indiana University in 2004. Based in Brooklyn, NY, she writes about science, health, and technology for researchers, the general public, and children.