CAREER: Quantifying How Peptoids Interact with Lipid Membranes

Santa Clara University, Santa Clara CA

Investigators

Abstract

In this CAREER project, funded by the Chemical Structure, Dynamics & Mechanisms-B Program of the Chemistry Division, Professor Grace Stokes of the Department of Chemistry and Biochemistry at Santa Clara University is investigating interactions between peptoids (a peptide-mimicking class of molecules with potential therapeutic and antibacterial properties) and cellular membranes. Information obtained from this research may be useful in assessing and predicting the potential health effects of peptoids. The results could lead to applications of peptoids in medical technologies, either as drugs or as components of biosensors or medical devices. The research is performed at a primarily undergraduate institution, where exposure of undergraduate students to authentic research experiences both in teaching and research labs engages a diverse cross-section of students, including women and underrepresented minorities. The research aims are integrated with undergraduate education activities, for example, students in a second-term organic chemistry teaching lab synthesize the library of water-soluble peptoids. Educational exercises utilizing research-derived data is developed to improve quantitative skills of first-generation college (FGC) students in general chemistry. Undergraduate research students are selected from the FGC student cohort in Professor Stokes' general chemistry course to work in her research lab. Through the research and educational activities, FGC students gain experience using modern laser spectroscopy methods and computational tools, which better prepares them for graduate school and future careers. Protocols and principles used to train undergraduate students to conduct nonlinear optical experiments and computational-guided inquiry exercises are broadly disseminated through workshops, websites, presentations, and publications to increase the participation of underrepresented minorities in the STEM workforce. Accurate models to predict membrane penetration by and accumulation of small organic molecules inform rational drug design. These models require a quantitative understanding of the thermodynamic forces which control interactions between lipid (fatty) membranes and molecules with varying hydrophobicity, charge, polarizability and 3-D structure. In this study, a diverse library of systematically-varied peptoids (N-substituted glycine oligomers) is synthesized. The impact of lipid composition on peptoid-lipid interactions is also probed using artificial plasma membranes. High-throughput experiments are conducted using nonlinear optical imaging and spectroscopy methods to determine how peptoid sequence and membrane composition impact the orientation and number of adsorbed peptoids. The thermodynamic dataset provides quantitative structure-function relationships which relate peptoid structure and lipid composition to free energies of adsorption. Complementary education activities integrate computational guided inquiry modules into general chemistry courses to improve quantitative skills and increase retention of first-generation college students in gateway courses for STEM majors. 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.