Collagen is the most abundant protein in humans, comprising 1/3 of the total protein and 3/4 of the dry weight of skin. Collagen abnormalities are associated with many human diseases, including arthritis. The overall objective of the proposed research is to reveal the chemical basis for the unique triple-helical structure of collagen, and t devise new therapies based on that knowledge.
Specific Aims : The four Specific Aims of this research proposal apply methods and ideas from physical organic chemistry, peptide chemistry, molecular self-assembly, chemical enzymology, and matrix biology.
Aim 1 is to discern whether enhancing a newly appreciated physicochemical force-the n->?* interaction-can increase triple-helix stability.
Aim 2 is to create collagen mimetic peptides that self-assemble into human-scale triple helices that are useful for biomedical applications.
Aim 3 is to gain insight into the mechanism of catalysis by human prolyl 4-hydroxylase, which is the enzyme that installs the prevalent and important 4-hydroxyproline residues in collagen strands and is a target for the treatment of fibrotic diseases. Finally, Aim 4 is to use extant knowledge of collagen to create peptide conjugates to assess and heal wounds in mice. Significance: The results of the research proposed herein will provide fundamental insights into the structure and conformational stability of the collagen triple helix, and will use those insights to create transformative molecular therapies for wound care, which now accounts for up to $15B annually in US health care costs, and other indications.

Public Health Relevance

This research project is focused on collagen, which is the most abundant protein in humans. Collagen abnormalities are associated with a variety of human diseases, including arthritis. The goal of the project is to obtain insights into the relationship between the amino acid sequence of collagen and its biological function (or dysfunction), as well as to create novel collagen-like proteins of therapeutic use in wound healing and other indications.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Tseng, Hung H
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University of Wisconsin Madison
Schools of Earth Sciences/Natur
United States
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Newberry, Robert W; Raines, Ronald T (2014) A key n??* Interaction in N-acyl homoserine lactones. ACS Chem Biol 9:880-3
Tanrikulu, I Caglar; Raines, Ronald T (2014) Optimal interstrand bridges for collagen-like biomaterials. J Am Chem Soc 136:13490-3
Newberry, Robert W; Bartlett, Gail J; VanVeller, Brett et al. (2014) Signatures of n??* interactions in proteins. Protein Sci 23:284-8
Chattopadhyay, Sayani; Guthrie, Kathleen M; Teixeira, Leandro et al. (2014) Anchoring a cytoactive factor in a wound bed promotes healing. J Tissue Eng Regen Med :
Chattopadhyay, Sayani; Raines, Ronald T (2014) Review collagen-based biomaterials for wound healing. Biopolymers 101:821-33
Choudhary, Amit; Newberry, Robert W; Raines, Ronald T (2014) n??* interactions engender chirality in carbonyl groups. Org Lett 16:3421-3
Kamer, Kimberli J; Choudhary, Amit; Raines, Ronald T (2013) Intimate interactions with carbonyl groups: dipole-dipole or nýýýýý*? J Org Chem 78:2099-103
Newberry, Robert W; VanVeller, Brett; Guzei, Ilia A et al. (2013) n??* interactions of amides and thioamides: implications for protein stability. J Am Chem Soc 135:7843-6
Newberry, Robert W; Raines, Ronald T (2013) nýýýýý* interactions in poly(lactic acid) suggest a role in protein folding. Chem Commun (Camb) 49:7699-701
Vasta, James D; Higgin, Joshua J; Kersteen, Elizabeth A et al. (2013) Bioavailable affinity label for collagen prolyl 4-hydroxylase. Bioorg Med Chem 21:3597-601

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