With support from the Organic and Macromolecular Chemistry Program at the National Science Foundation for this new award, Professor Felicia Etzkorn, of the Department of Chemistry at Virginia Polytechnic Institute, will develop new materials inspired by the molecular structure of the biopolymer, collagen. This research in the laboratories of Professor Felicia Etzkorn in the Department of Chemistry at Virginia Tech will contribute to a fundamental understanding of the molecular forces that cause formation of the collagen triple helix, while leading to interesting new materials with potential bioengineering applications. Collagen?s unique macroscopic properties of strength and flexibility make it an attractive target for mimicry. The basic sequence of collagen that promotes triple helix formation is: glycine-proline-hydroxyproline (Gly-Pro-Hyp). Both Gly-Pro and Xaa-Hyp sequences are required to be in the trans conformation for the triple helix. The materials were designed to stabilize the collagen triple helix structure by replacement of the key Gly-trans-Pro amide bond with a Gly-trans-Pro alkene isostere to decrease the entropy of folding. Peptides with alkene isostere replacements will be synthesized to elucidate the physical and structural perturbations introduced by the substitution. Polymer synthesis experiments will follow two threads: polymer length, and triple helix stabilization. These materials will be characterized for stability and for mechanical strength and biocompatibility by a collaborator, Prof. Joseph Freeman. Once stable, folded collagen-like polymers have been synthesized, alternative tripeptide monomers will be introduced including charged residues: Lys, Arg, and Glu, to bind counterions in processes similar to biomineralization
Professor Etkorn will make contributions to society through education, dissemination of results, and applications. Both graduate and undergraduate students will continue to be trained during their contributions to the project. The Etzkorn group has had success recruiting female, minority, and underprivileged students, each of whom has pursued a career in scientific research or professional school. This project will continue to recruit one underrepresented undergraduate student each summer through the Multicultural Academic Opportunities Program of Virginia Polytechnic Institute. The primary collaborator on this project, Joseph Freeman, is an Assistant Professor of Biomedical Engineering at Virginia Tech who is African-American. The broader impact of this research will continue to focus on applications of these new materials in bioengineering, and be disseminated through presentations at national meetings, publication of original research, and review articles in high quality journals, and patent applications. The results of this basic research into the fundamental properties of collagen, and the development of synthetic collagen-inspired materials are expected to lead to new and exciting applications.
Collagen Inspired Polymers Intellectual Merit Collagen is a highly abundant fibrous protein, constituting approximately one third of all protein in vertebrates. Collagen is the scaffolding material found in skin, bones, tendons, cartilage, blood vessels and nearly all organs where it serves to form a matrix for holding and supporting cells. It has the properties of elasticity and strength. Polymers inspired by collagen would be expected to possess similar properties. These polymers may find application where rigidity is not desired, while fibrous strength and elasticity are desirable. Collagen exists primarily as a triple helix of three protein strands, like a rope. The stability of the triple helix is important in understanding the physical properties of collagen. Peptide bonds that link the amino acid, proline, to another amino acid can exist in two shapes, cis and trans, at the amide bond. Collagen has a very high proline content and requires the trans shape for the triple helix. We wondered if the triple helix would be more stable if we replaced the proline amide bond with a trans-locked analogue that cannot switch between the cis and trans shapes. We found that the replacement destabilized the collagen triple helix instead of stabilizing it. This led to a new hypothesis that the polarity of the amide bond, and the specific interactions between the atoms in the protein strands are important for the stability of the collagen triple helix. Molecular modeling studies were then used to design new trans-locked proline analogues to stabilize collagen and study its physical properties in more detail. Broader Impacts Two graduate students, two post-doctoral associates, one technician, and four undergraduates were trained in collagen theory, organic and peptide synthesis, and/or molecular modeling on this project. Two of these laboratory workers became pregnant and delivered healthy babies while working on this project. Each of the students has continued her or his studies in another program or department. We have continued our collaboration with an underrepresented faculty member, and his graduate student, who is also an underrepresented minority member. During the period supported by this grant, the PI developed a statement of safety and support for pregnant laboratory workers in the department, which was recently passed by a majority of the faculty and incorporated into the departmental web site. This work resulted in two publications with a third in progress, and presentations at one national and one international meeting.
