CAREER: Enabling nanodisc native mass spectrometry to study membrane active compounds

Cells within the human body are consistently under attack by invaders, which include bacteria, viruses, and certain molecules in the environment. While it is known that membrane-active compounds (MACs) defend human cells by interacting with the invader's cell membranes, exactly how they do this is still unclear. Dr. Michael Marty of the University of Arizona uses mass spectrometry to gain an understanding of membrane-active compound behavior and thus, provides fundamental insight into how the body's immune system functions. This project uses new mass spectrometry tools to determine how MACs change the structure and stability of cell membrane mimics. A set of integrated educational activities provide professional training in mass spectrometry data analysis while engaging military veterans in science education and research activities. The program eases the transition of veterans from military service to higher education, promotes persistence in STEM education (STEM), and broadens participation in research. Tutorials are also created to enhance the educational infrastructure and broaden the dissemination of data analysis technologies.<br/><br/>With this award, the Chemistry of Life Processes Program, with co-funding from the Chemical Measurement and Imaging Program, is funding Dr. Michael Marty at the University of Arizona to study membrane-active compounds (MACs) that directly target lipid membranes. In the past, these mechanisms of action were not well understood because it is difficult to quantify MAC interactions within membranes. Dr. Marty is addressing this challenge through the development of novel chemical measurement techniques based on native mass spectrometry (MS) methods and lipoprotein nanodisc membrane mimetics. By measuring the mass of the entire nanodisc assembly with embedded MAC complexes, it is possible to characterize the oligomeric states of MACs in different lipid environments. This CAREER project provides the foundation for these experiments by uncovering the mechanisms of nanodisc stability under native MS conditions, creating native MS-compatible nanodiscs that model natural membranes, and developing algorithms for the analysis of complex MS data. The research objectives are integrated with two educational objectives that involve the engagement of undergraduate military veterans in STEM research and the development of professional education tutorials.<br/><br/>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.