Synthesis, assembly, and properties of dehydroalanine containing block copolypeptides

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With the support of the Macromolecular, Supramolecular and Nanochemistry program in the Division of Chemistry, Professor Timothy J. Deming of the University of California-Los Angeles is preparing and studying the aqueous self-assembly of synthetic copolypeptide amphiphiles containing dehydroamino acids. Polypeptides are among the most important biopolymers and are basically long chain macromolecules consisting of amino acids linked together by a particular kind of a chemical bond called a peptide bond or link. All living organisms contain numerous polypeptides and cannot exist without them. Amphiphilic copolymers, on the other hand, are polymers that possess both water-loving and oil-loving properties. They are typically found in soaps and detergents and are also the main component of cell membranes. In this research, copolypeptides containing dehydroalanine segments will first be synthesized using a suite of chemical reaction sequences. The assemblies of these polymers will then be investigated in water in order to understand how the extended conformation of hydrophobic (oil-loving) dehydroalanine segments influences assembly structure. The synthesized polymers will also be subjected to chemical modifications in order to further understand structural changes in these assemblies when they are exposed to biological conditions that mimic those found in the human body. These studies have the potential to advance the knowledge on self-assembly of complex biopolymers and are also of relevance to the development of stimuli responsive biomaterials for therapeutic delivery applications. The research will provide interdisciplinary teaching and training of graduate and undergraduate students and unique opportunities for inclusion of underrepresented groups. The team will continue interactions and outreach with local universities with majority Hispanic student populations. Participations in “Meet the ACS Editors” events at national conferences will afford advice on preparation and review of manuscripts to young scientists and encourage URM and female junior faculty to participate in journal activities and organize ACS National Meeting symposia. This research will focus on the design, synthesis and systematic study of self-assembly of novel diblock copolypeptide amphiphiles containing poly(dehydroalanine) (ADH) segments in order to learn how the extended conformations of ADH chains of varying lengths influence self-assembled structures. Following the identification of compositions useful for the formation of ordered assemblies, ionic hydrophilic segments will be replaced with non-ionic and biocompatible poly(L-methionine sulfoxide). This modification will enable evaluation of simultaneous switching of conformation and solubility in copolypeptides. The use of non-ionic segments is also expected to impart improved downstream cell and animal compatibility. All copolypeptides will be purified by dialysis and characterized using a suite of chromatographic and spectroscopic techniques. Lastly, a biomimetic chemical modification of ADH and other segments in block copolypeptides will be investigated in order to further understand how assembled structures respond to changes in both segment conformations and solubilities. Outcomes of these studies will provide new insights on how chain conformation switching under biologically relevant conditions can enhance the development and advancement of stimuli responsive biomaterials, in particular those amenable for intracellular therapeutic delivery. The methodology developed in this research significantly lowers the barriers for synthetic access to ADH-containing copolymers. Coupled with in-depth examination of the relationships between copolypeptide composition and self-assembled structures, the knowledge gained has the potential to advance the field of biomimetic polymers.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.