Understanding Key Interactions between Lipid Membranes and Peripheral Membrane Proteins Involved in Cellular Signalling

Abstract

Lipid-protein interactions play a key role in formation of protein complexes at the membrane surface. This is of particular importance for many systems involved in cellular signalling. This has been shown experimentally, and, in many cases, been verified and complemented by molecular dynamics (MD) simulations. We have previously used MD simulations to study Pleckstrin homology (PH) domains interacting with phosphatidylinositol (PIP)-containing membranes. Using coarse-grained simulations, we could map out binding sites, and investigate the effects of simultaneous binding at multiple sites (Naughton, Kalli and Sansom, 2018, J. Mol. Biol., 430, 372-388). Binding affinity were estimated using free energy calculations, and compared to experimental values. This work has provided an in-depth understanding of protein-lipid binding for the PH family. In the current study, we extend our investigations to other families of membrane-binding proteins. We have investigated the C2 domain from the notch ligand system, C2 from PTEN, and the FYVE domain from EEA1. The C2 domain binds to membranes without PIP, and thus these studies of C2 may characterise new classes of membrane-protein interactions. Our studies have so far led to development of methods for more efficient sampling strategies, meaning that it is now feasible to study a larger range of proteins and protein families, and to extend simulations to larger systems with multiple domains. Key questions to be addressed include: what lipids are important for the membrane-protein interactions in various systems; how do binding free energy landscapes compare across different families of membrane-binding proteins; and what is the synergistic effect of multiple domains interacting with nanoclusters of lipids in the membrane?