"Membrane Protein Interactions with Lipids as Viewed by Molecular Simulations"
Interactions with lipids are important in the function of membrane proteins  and in the organization of cell membranes. Molecular dynamics simulations allow us to explore structural, energetic, and dynamic aspects of these interactions. Coarse-grained (CG) simulations in mixed lipid bilayers allow identification of lipid interaction sites, which may be probed further by estimation of free energy landscapes to explore lipid specificity, and by atomistic simulations to refine models of the structure and dynamics of lipid binding. This approach has been applied to a number of membrane proteins, including transporters, ion channels, and receptors. Simulations of lipid interactions with Class A GPCRs has revealed binding sites for cholesterol and PIP2, subsequently confirmed by both MS  and structural data. Interactions with PIP2 have been shown to be dependent on the activation state of the receptor, suggesting a functional role for the lipid via allosteric modulation . Interactions of lipids with other classes of GPCRs have been explored, including of cholesterol and PIP2 with the Class F GPCR Smoothened . Our analysis of the interactions of lipids with ion channels have also focussed on cholesterol and PIP2, both of which are allosteric modulator of a number of ion channel families. PIP2 interactions have been characterised for Kir channels, and more recently for members of the TRP channel family . Simulations of large membrane systems containing multiple copies of Kir channels suggest that the lipid composition of the bilayer can modulate channel-channel interactions within crowded membranes.
 Duncan et al. (2020) Lipid-dependent regulation of ion channels and GPCRs: insights from structures and simulations. Ann. Rev. Pharmacol. Toxicol. 60:31-50.
 Yen et al. (2018) PtdIns(4,5)P2 stabilises active states of GPCRs and enhances selectivity of G-protein coupling. Nature 559: 423–427.
 Song et al. (2019) State-dependent lipid interactions with the A2a receptor revealed by MD simulations using in vivo-mimetic membranes. Structure 27: 392–403;
 Hedger et al. (2019) Cholesterol interaction sites on the transmembrane domain of the hedgehog signal transducer and Class F G protein-coupled receptor Smoothened. Structure 27: 549-559.
 Wang et al. (2020) Lipid interactions of a ciliary membrane TRP channel: simulation and structural studies of polycystin-2. Structure 28: 169-184.
26 February 2020, 11:00 (Wednesday, 6th week, Hilary 2020)
Wellcome Trust Centre for Human Genetics, Headington OX3 7BN
Meeting rooms A & B
Prof Mark Sansom (University of Oxford)
Wellcome Trust Centre for Human Genetics
Agata Krupa (Wellcome Centre for Human Genetics, University of Oxford)
Organiser contact email address:
Prof Yvonne Jones (University of Oxford)
Members of the University only