Timothy J. Deming - US grants

This research program focuses on the discovery and study of new metal-catalyzed methods for the synthesis of polypeptides with unique stereochemistry and structure. By identification of active intermediates, the mechanism of ruthenium/rhodium/iridium amido-sulfonamide initiated alpha-amino acid N-carboxyanhydride polymerizations will be elucidated. The origins of the stereochemical selectivity of these polymerizations will be addressed through studies of the dynamics of and monomer and ligand influences on the stereochemistry of the chiral metal active species. These discoveries will then guide the development of new initiators that will allow complete control of polypeptide stereochemistry, including the formation of alternating D/L stereocopolymers.

With the support of the Organic and Macromolecular Chemistry Program, Professor Timothy J. Deming, of the Departments of Chemistry and Materials Science at the University of California, Santa Barbara, is studying new catalytic techniques for polypeptide synthesis, offering promise for the selective and efficient synthesis of complex polypeptides with unique molecular architectures. Polypeptides represent one of the major classes of macromolecules utilized by living organisms. These large molecules, comprised of many amino acids linked together, display a wide range of important physical and chemical properties. New approaches to the preparation of polypeptides offer promise for the efficient synthesis of molecules anticipated to display new and/or unusual properties, particularly in the development of new catalysts for selective molecular transformations.

This award is funded under the American Recovery and Reinvestment Act of 2009 (Public Law 111-5)

This award by the Biomaterials program in the Division of Materials Research to University of California Los Angeles is to develop and study multifunctional amphiphilic block copolypeptides that can be assembled into vesicle and emulsion vehicles containing functionality for intracellular drug delivery. The proposed copolypeptide design, synthesis, development and testing, as well as the functionality and versatility inherent in these polypeptides will be used to create multifunctional vehicles with properties suitable for drug delivery applications. The key challenge of this proposal is to design and prepare polypeptide amphiphiles with added functions without adversely affecting other functions or physical features, to obtain true multifunctional vesicle and emulsion carriers. The knowledge gained from these studies will allow fine tuning of carrier properties for downstream specific uses in encapsulation and delivery of drugs. Students trained under this program will be valuable in the industrial job force (both pharmaceutical and materials science areas) since they will learn fundamentals of polymer synthesis using catalysis and self-assembly, cell culture and intracellular trafficking of drug carriers, as well as more applied areas of materials characterization and property evaluation. The PIs will also continue their academic activities in developing curricula and teaching in bioengineering for both graduates and undergraduates, and involve concepts and laboratory methods.

The proposed design, synthesis, development and testing of copolypeptides are expected to produce vesicles with enhanced and multifunctional properties for drug delivery systems. These vesicles are expected to have adequate size, shape, good cell uptake and stability, and cargo loading capacity for drug delivery. The design and synthesis of improved drug delivery vehicles expected from these studies are of broad importance for the pharmaceutical industry, and for human health in general. The academic impact of the proposal is in developing curricula and teaching tools for graduate and undergraduate students.

ID: DMR-1063924 PI: Deming, Timothy ORG: University of California, Los Angeles

Title: 2011 NSF-DFG Research Conference: Bioinspired Design and Engineering of Novel Functional Materials

INTELLECTUAL MERIT: This award supports the sixth DFG-NSF Research Conference to be held in New York City in March 2011. The objective of the conference is to stimulate US-German international research collaborations in the area of bioinspired design and engineering of novel functional materials. This will be the sixth in a series of DFG-NSF Research Conferences, a series conceived and promoted by the immediate past-Director of NSF and his counterpart at the DFG. The conference will be held at the German House on United Nations Plaza, which houses the offices of the German Government in New York City. The structures found in nature are admired for the elegant way that material is matched to function. Recent advances have begun to reveal the strategies used by living systems to create the materials from which these structures are built. It is now realistic to consider new approaches to design and engineering of functional materials that are inspired by the lessons learned from biological structures and the means by which they are created. The emphasis will be on the formation of functional synthetic materials using biological, biomimetic, and bioinspired templates, approaches, or pathways. The longer-range goal is to create robust routes for the synthesis of materials with novel combinations of properties or possessing functionalities that are unachievable by conventional means. This work calls for an interdisciplinary approach involving close collaboration among scientists from a broad range of disciplines including biology, chemistry, physics, and materials science and engineering. In addition, the use of state-of-the art genetic and computational methods and processing and characterization approaches is essential to transferring the understanding of fundamental principles into the successful creation of novel functional materials.

BROADER IMPACTS: The longer-term societal outcomes expected from the conference include development of new functional materials that can be achieved by mimicry of biological systems and processes. A broader impact specific to this conference is the opportunity to foster US-German scientific collaborations. The program has been specifically designed to promote informal discussions among the participants as they seek to identify potential collaborative partners. The program is designed to maximize opportunities for informal discussion of possible collaborations, and the conference is organized without parallel sessions so that all participants have an opportunity to be exposed the full range of activity represented in the presentations.

SUPPORT: This conference is supported jointly by the MPS/DMR Biomaterials Program, the MPS/DMR Office of Special Programs, the ENG/CBET Biomedical Engineering Program, and the NSF Office of International Science and Engineering(OISE).

In this project funded by the Macromolecular, Supramolecular and Nanochemistry Program of the Chemistry Division, Timothy Deming of the University of California at Los Angeles will develop strategies for the addition of sugar functionality to peptide based polymers. Sugar functionalized amino acid monomers will be prepared with different chemical linkages for sugar attachment, and methods for efficient polymerization of these monomers into a variety of polypeptide architectures will be developed. The different sugars and linkages employed will be used to control the presentation of biomolecular functionality and to influence the macromolecule's interactions with other polymers and biomolecules. This project will be performed in collaboration with Henning Menzel at the Technical University of Braunschweig, Germany, Helmut Schlaad of the Max-Planck-Institute for Colloids and Interfaces, Germany, Sebastien Lecommandoux of the University of Bordeaux, France, and Andreas Heise of the Dublin City University, Ireland. Together, these groups will combine their separate areas of expertise to prepare and study sugar functionalized polypeptides of unprecedented order and hierarchical complexity. The broader impacts involve the development of infrastructure for research and education through the creation of new multilateral international collaborations, the promotion of this growing field via organization of an international symposium on sugar-functionalized polymers, and the promotion of teaching, training and learning of graduate students through this research project and an international exchange of ideas and expertise.

This work will expand the repertoire of chemistry that can be used to create new polymers that mimic natural biomaterials. The results of these studies could have many important long term impacts on a variety of applications and industries in which biomimetic polymers are important, including drug delivery, regenerative medicine, and medical diagnostics.

In this project funded by the Macromolecular, Supramolecular and Nanochemistry Program of the Chemistry Division, Timothy Deming of the University of California at Los Angeles will study how to utilize different types of initiation chemistries and polymerization catalysts in one reaction to generate branched polypeptide architectures ranging from cylindrical brush to hyperbranched. The approach is to employ different initiation chemistry, different monomers (N-carboxyanhydrides and their sulfur derivatives), and different nickel and cobalt polymerization catalysts to control the relative initiation rates of the added free initiator versus ones that are tethered to the side chain of the monomer. In this manner, a range of polymer architectures can be prepared by controlling the amount of propagation that occurs from each type of initiating site. The broader impacts involve advancing teaching, training and learning in interdisciplinary bioengineering at UCLA as well as participating in recruiting underrepresented minorities to pursue advanced STEM degrees.

This work will enhance our fundamental understanding about how to easily prepare polypeptides, the basic component of proteins, which have different types of branched structures. The results of these studies could have many important long term impacts on applications in which protein-based materials are important, including drug delivery, tissue engineering, and other areas of biotechnology.

Technical: There is a need for polymeric drug carriers that can be prepared using a versatile method that allows fine tuning of chemical composition and structure, and use building blocks that are biocompatible and easily functionalized. The goal of this project is to develop and study multifunctional amphiphilic block copolypeptides containing modified poly(L-methionine) segments, MMOD, that can be assembled into vehicles for intracellular drug delivery. Recent synthetic advances in this lab now allow the development of entirely new polypeptide amphiphiles utilizing MMOD domains that are designed so that individual segments can play unprecedented multiple functional roles in the resulting nanocarrier assemblies. This innovative approach provides a new method for introducing functionality into polymeric nanocarriers and will develop and test a new class of methionine based biomaterials. The incorporation of methionine segments and their subsequent modification is a straightforward, scalable process, and allows unprecedented control in the ability to add complex functionality and biological activity to polypeptides. Some MMOD residues also occur naturally in biological systems and these will be used strategically to promote release of therapeutics, and may also provide other therapeutic benefits. The MMOD segments will be utilized as new, functional hydrophilic domains capable of providing multiple combinations of solubility, biocompatibility, therapeutic binding, cell uptake, enzyme-response, pH response, and chemoselective bioconjugation. Specifically, the project will design, prepare, and characterize vesicle forming block copolypeptides containing MMOD segments as carriers for therapeutics with low cytotoxicity and capability for cell uptake, endosomal release and intracellular carrier disruption. In addition, it will test the capabilities of these carriers using in vitro cell culture and trafficking studies. The knowledge gained from these studies will allow fine tuning of carrier properties for downstream specific uses in encapsulation and delivery of drugs, and will lay groundwork for development of a new class of functional biomaterials for medical applications.

Non-Technical: In this project, the PIs will continue their successful inclusion of underrepresented groups, teaching and training of graduate and undergraduate students, and dissemination of their research findings in publications and presentations. Some examples of these efforts from the previous grant period are: development and improvement of bioengineering courses incorporating concepts from the project such as intracellular trafficking and bioconjugation methods; recruitment of a Hispanic female student (Ph.D. granted in March 2013) and an African American female student for this project (1st year); PI and student presentations of research results at national and local meetings (ACS, BMES, MRS, Society for Advancement of Hispanics, Chicanos, and Native Americans in Science (SACNAS) national meeting); and presentations incorporating this research by the PI to encourage students to pursue careers in science (2010 UCSB Summer School on materials synthesis; 2011 NAE Grand Challenges Summit for graduate students; 2012 International Young Scientist Symposium, Bordeaux, France). Professor Kamei has also made annual visits to elementary and high schools in East Los Angeles (one is 90% Hispanic) to inspire youth in this system to become scientists and engineers. Ph.D. students trained under this program are valuable in the industrial job force (both pharmaceutical and materials science areas) since they will learn fundamentals of polymer synthesis using catalysis and self-assembly, cell culture and drug trafficking, as well as more applied areas of materials characterization and property evaluation. These undergraduate students have also done well by being admitted into prestigious Ph.D. (Washington, MIT, UCSB) and MD (Cornell, Texas A&M) programs, and obtaining NSF graduate fellowships.

Polypeptides are chemically synthesized mimics of natural proteins, and offer many advantages as mimics of biological materials for medical uses. Since they are synthetic, these materials are free from biological impurities that may have undesirable properties, and also are prepared free from pathogens that may be carried in biologically derived materials. Chemical modification of polypeptides is a method to enhance the properties of these materials for eventual use in applications such as drug delivery vehicles, regenerative medicine scaffolds, or as medical diagnostic devices. This research project is focused on improving upon the current state of the art for chemical polypeptide modification to make these processes more economical and broader in scope. Success of this project is expected to provide general methods that may be used downstream in a number of medically important applications. In this project, Prof. Timothy Deming at the University of California Los Angeles plans to include underrepresented groups, teach and train graduate and undergraduate students, and disseminate research findings in publications and presentations.

Under the support of the Macromolecular, Supramolecular and Nanochemistry Program of the NSF Division of Chemistry, Prof. Deming conducts research to (i) develop practical, selective methods to chemically modify polypeptides, and (ii) develop this chemistry for controlled attachment and release of molecules from polypeptides. More specifically, his research group plans to explore and develop the reactions of methionine residues in polypeptides to prepare aklylated methionine sulfonium derivatives. The key challenge of this project is to determine how alkylating reagent structure affects the chemistry and stability of the resulting methionine sulfonium groups. The knowledge gained from these studies can allow fine tuning of polypeptide functional group reactivity that may be valuable for downstream specific uses, e.g. in the controlled release of drugs, and is expected to lay groundwork for development of a new class of functional biopolymers.

Coacervation is a process by which attractive electrostatic forces between positive and negative groups on long macromolecules called polyelectrolytes cause their aggregation and separation out of a mixture with water as a polyelectrolyte coacervate. These coacervates have similarities to cellular organelles that contain intrinsically disordered proteins and are not encapsulated in a membrane, hence their being named "membraneless organelles". Protein coacervates have been linked to many important biological processes and are also known to be key components of moisture-resistant adhesives produced by marine organisms, which have applications in medicine as surgical sealants. There is also considerable interest in use of coacervation to create materials that can be used as drug carriers, cell scaffolds, or for engineering applications. The research group of Professor Timothy Deming at University of California Los Angeles is developing a new class of coacervate-forming polypeptides, which are synthetic mimics of natural proteins and whose properties can be rapidly tuned for specific uses. The study of coacervate-forming polypeptides can be used in the efforts to better mimic and understand the physical behavior of disordered proteins and to prepare bioadhesives and biologically-inspired artificial organelles. This project is also contributing to the development of human resources in science, technology, engineering and mathematics. Specifically, the PI provides mentorship to the members of the International Society for Pharmaceutical Engineering Student Chapter at UCLA. He also trains bioengineering undergraduate students who work on interdisciplinary projects in an engineering lab and who have a medical school collaborator. The PI mentors in research high school students who participate in the Engineering Science Corps Outreach Program of the UCLA School of Engineering. This summer research program is designed to bring local underrepresented minority students from the LA area in research labs at UCLA where they learn about, and prepare for, careers in engineering.

This project is focused on the (i) design, preparation and characterization of polypeptides whose sidechains makes them good mimics of coacervate-forming proteins and allows their properties to be tuned or switched, and on the (ii) design, preparation and characterization of block co-polypeptides that contain distinct hydrophilic and alpha-helical coacervate-forming domains and can form hydrogels responsive to environmental stimuli, such as the temperature and pH. The research team works to identify the molecular parameters that control the response of the molecules to temperature and pH. A pioneering aspect of this research is that the block copolypeptides can have multiple individual chain segments, each sensitive to temperature, ion, or redox changes; hence combinations of stimuli can generate different responses in the assemblies. The proposed materials are designed to form hydrogels. The material's ability to respond to environmental stimuli confers them potential utility in biology.

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.

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.