Investigating the impact of lipid-protein interactions in membrane protein structure and conformational dynamics

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Membranes are the walls around cells and membrane proteins are the doors and the windows that allow passage of information and molecules across the wall. How do the walls (membrane) and windows (membrane protein) interact? Membranes are a complex mixture of lipids that interact directly with membrane proteins. The general principles of these interactions and how these interactions modulate membrane protein structure and function is largely unknown. In the last decade, there has been a surge of membrane protein structures that provide snapshots of what these proteins look like and provide a platform to hypothesize how these proteins carryout their functions. Often neglected in these hypotheses is the role of the lipid bilayer because of the lack of general principles describing lipid-protein interactions and straightforward experimental methods for determining these interactions. A systematic analysis of the impact of lipids on structure and conformational dynamics is needed and is provided in this project. The results of this research will impact many fields beyond molecular biophysics such as cell signaling and regulation, molecular assembly, and lipid metabolism and homeostasis. Through the research and educational goals of the project, the PI will impact the broader community by focusing on initiatives that (i) increase the participation of underrepresented groups in undergraduate STEM research and (ii) catalyze the use of effective and inclusive practices in undergraduate STEM education.To investigate general principles, two very different membrane proteins (both in structure and function) are investigated. The use of systematic variation of physical aspects of the membrane environment have been established to design experiments which address specific questions associated with lipid segregation and membrane mimic properties. Combined, the approaches, which utilize a variety of biophysical methods described in this project will determine if the lipid boundary is critical to membrane protein structure and function. The results of this research will provide a fundamental understanding and establish general principles for the role of lipid - protein interactions in (i) stabilizing membrane protein folds and (ii) facilitating conformational dynamics involved in catalysis. These results will impact the in vitro preparation of membrane proteins, the interpretation of membrane misfolding mutations, the assemblies of biomolecular complexes in the context of membranes, clustering in the membrane, and much more.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.