Investigation of Nanodiscs as a Membrane Protein Environment

Nanodiscs are a synthetic model system for studying the behavior of cell membranes. They are used in experimental biological research to understand structural and functional properties of membrane proteins. Their utility is chiefly due to their water solubility and a relative native lipid environment for membrane proteins compared to other synthetic membrane systems. Though membrane proteins are frequently solubilized and stabilized in a nanodisc environment, the physical conditions that they are exposed to in a nanodisc have not been studied in detail. Additionally, the dynamic behavior of transmembrane proteins in a nanodisc environment has not been characterized with respect to a more typical planar bilayer environment. The results presented in this thesis formulate an answer to these open questions through atomistic molecular dynamics simulations and machine learning methods. Nanodiscs and bilayer systems with identical lipid compositions are systematically studied, and separately, both types of systems with adenosine receptor A2AR to understand the differences between the model systems. The membrane environment in the two systems is characterized by two well understood physical properties: the order parameter, and the diffusion of lipids in the membrane. The results not only affirm previous studies of nanodiscs but also provide novel insights into the membrane environment of the nanodisc systems. Finally, with the help of machine learning methods, the dynamical behaviour of the protein is shown to be significantly altered in the nanodisc system when compared to a planar bilayer environment. Specifically, it is shown that the activation behavior of A2AR is dependent on model system used to reconstitute the protein