Biophysical Effects of Reversible Lipid Modification of Integral Membrane Proteins

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There is growing evidence that integral membrane proteins, which represent approximately 30% of the proteins in the human body, undergo lipid modifications to maintain their healthy biological function. However, how lipidation regulates the function of the membrane proteins is not well understood. This project will uncover the effect of lipid modification on these integral membrane proteins. Using computer modeling and simulations, the project will study the changes in protein structure due to the attachment of the lipid. The project will also examine the interaction of the protein with other integral membrane proteins and the change in their biological activity in the presence and absence of the attached lipid. The project involves concepts from many disciplines, including chemistry, biology, physics, mathematics, and computer science, and provides an excellent opportunity to train students with different academic backgrounds. The project will provide scientific training to undergraduate students through a cohort-based approach that will engage a team of 5–10 undergraduates in a ten-week summer research project. The project will focus on recruiting and better preparing underrepresented minority students for graduate school. Students will be equipped with research experiences, fundamental knowledge, and professional skills to successfully transition to doctoral programs in STEM disciplines.This research project is motivated by a lack of knowledge pertaining to the molecular biophysics of the interplay of lipids and proteins—the structural and functional workhorses of life. The focus will be on palmitoylation, the covalent attachment of palmitic acid to a protein's cysteine residue via a thioester bond. The addition of palmitoyl chain(s) regulates a protein's dynamics and biological function by altering specific protein-protein and protein-lipid interactions. The project will (i) characterize the impact of palmitoylation on protein's structure using all-atom simulations to investigate the structural and chemical asymmetry introduced in proteins by the addition of palmitoyl chains; (ii) compute the influence of palmitoylation on protein-lipid dynamics via multiscale simulations to elucidate palmitoylated protein dynamics over tens of microseconds, and tens of nanometers in biomimetic cellular and subcellular membrane environments; and (iii) evaluate the consequence of palmitoylation on protein function via the application of the newly developed and validated protein association energy landscape (PANEL) method to capture protein assembly. Results obtained will be verified by data-sharing collaborations with experimental research groups. The use of an extensive computational toolkit and bioinformatics approaches with in vitro experiments will establish the fundamental structural-functional and dynamical aspects of palmitoylated membrane proteins in their lipid landscapes.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.