Membrane fusion is a fundamental chemical transport process in cell biology. While much attention has been devoted to understanding the native protein machinery governing fusion, fewer efforts have been made in development of synthetic approaches towards understanding membrane fusion. It is thought that, generally, the specificity of native fusion derives from the coupling of surface recognition with local membrane disruption or strain. However, most fusion studies have been carried out on specific native fusogenic systems that employ similar recognition motifs. This project focuses on membrane fusion as a noncovalent chemical reaction rather than a biological event. The project will promote understanding of the physical fusion process through the development of synthetic (non-native), small molecule fusogenic systems that allow controlled studies of membrane fusion parameters and establish the generality of recognition triggered membrane fusion. The project focuses on a synthetic and minimal membrane fusion system that is subject to mechanistic dissection through chemical modification and examination. This model system provides an opportunity to closely study fusion not afforded by more complex biological systems in which there are multiple regulatory factors involved that obscure and complicate analysis. Membrane fusion is one method Nature uses for selective, controlled chemical delivery. Development of a synthetic membrane fusion system contributes directly to understanding of biomembrane fusion and additionally may lead to a strategy for targeted drug delivery and nanoscale compartmentalized chemistry. This research will therefore impact multiple fields of study.
Broader Impact This cross-displinary project promotes expansion of non-covalent chemical thinking through the development of new undergraduate and graduate classes in noncovalent chemistry. Most significantly is the development of an NSF-REEL (Research Experiences to Enhance Learning) module where undergraduate students will participate in the synthesis and functional evaluation of a peptide library based on the HIV-fusion peptide sequence. The goal is to probe the functional role of flexibility of the HIV-fusion peptide, and the REEL module is ideal for involving undergraduates in novel research while simultaneously providing instruction on peptide, membrane and noncovalent chemistry. This educational module will integrate topics from sophomore organic chemistry with research on the HIV membrane fusion mechanism, underscoring the importance of basic chemistry. Basic chemistry will also be marketed through on-campus outreach activities, which will be achieved through partnership with on-campus student leadership. Using an existing program of educational events scheduled by minority student organizations, a quarterly series of informal and general seminars will be held at campus residence halls to introduce students to possibilities in science at Ohio State University, including this project. The project integrates basic research with educational appeal and interest. The easily imagined biomedical applications of membrane fusion research to targeted chemotherapy and HIV research should inspire students to participate. The project also includes an outreach program for minority high school students using minority student participants as ambassadors in an existing program where college students visit high schools to perform scientific demonstrations.
Membrane fusion is a fundamental chemical transport process in cell biology. While much attention has been devoted to understanding the native protein machinery governing fusion, fewer efforts have been made in development of synthetic approaches towards selective membrane fusion. Membrane fusion itself is a noncovalent reaction in water; this class of chemical reactivity represents a complex problem that has not been a traditional focus of organic chemistry. Despite this history, there is a critical role to be played by organic chemists in the investigation of membrane fusion. Chemical investigation into the scope and limitations of this noncovalent reaction (fusion) has only just begun, with discovery of methods to elicit marginal reactivity. Intellectually, it is useful to re-frame the phenomenon of membrane fusion as a tractable synthetic transformation; albeit the transformation of an assembly of molecules. This research program yielded artificial membrane fusion systems, and used these systems as biomimetic tools to understand how membranes fuse. The determinants of fusion were studied and a chemical blueprint for functional fusogenic systems was drafted. Overall, while these studies on synthetic systems contribute directly to the understanding of biomembrane fusion there are also novel chemical concepts discovered that are applicable to targeted chemical delivery, controlled release, polymer assemblies and nanoscale compartmentalized chemistry—it is anticipated that this research will impact those fields of study.
