ABSTRACT: A significant fraction of peripheral membrane proteins has structural flexibility with biomedical implications. Neutron reflectometry is a suitable method to structurally characterize ensembles of such membrane-bound proteins in a biomimetic environment, albeit at low spatial resolution. I will review our longstanding method developments in supported lipid membranes and biological neutron reflectometry [1], and introduce a computational framework for experimental optimization using information theory [2]. I will then highlight recent progress in integrative membrane-protein structure modeling, combining thermodynamic studies, complementary structural techniques, and molecular simulations to derive a high-resolution, dynamic structural model relevant to biomedical applications. I will demonstrate these methods using the cancer-related KRAS [3] and Arf [4] proteins and the HIV-1 accessory protein Nef.
[1] Eells, R. et al. Structural investigations of membrane-associated proteins by neutron reflectometry. in Characterization of Biological Membranes (eds. Nieh, M.-P., Heberle, F. A. & Katsaras, J.) 87–130 (De Gruyter, 2019)
[2] Treece, B. W. et al. Optimization of reflectometry experiments using information theory. Journal of Applied Crystallography 52, 47–59 (2019).
[3] Heinrich F. et al. Membrane-Bound KRAS Approximates an Entropic Ensemble of Configurations. Biophysical Journal 120:4055 (2021)
[4] Soubias O. et al. Membrane surface recognition by the ASAP1 PH domain and consequences for interactions with the small GTPase Arf1. Science Advances 6:eabd1882 (2020)
LINK: https://uchicago.zoom.us/j/94220080385?pwd=b0VpcUFUOFNDT0pITk5WeTg4YjAwZz09
Meeting ID: 942 2008 0385
Password: 013444