Prof Mark Sansom's seminar "Membrane Protein Interactions with Lipids as Viewed by Molecular Simulations"

Prof Mark Sansom is from the Department of Biochemistry, University of Oxford. More information about him can be found here 

Venue: WCHG meeting rooms A & B

Abstract: 

Interactions with lipids are important in the function of membrane proteins [1] 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 [2] 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 [3]. Interactions of lipids with other classes of GPCRs have been explored, including of cholesterol and PIP₂ with the Class F GPCR Smoothened [4]. 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 [5]. 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.

[1] Duncan et al. (2020) Lipid-dependent regulation of ion channels and GPCRs: insights from structures and simulations. Ann. Rev. Pharmacol. Toxicol. 60:31-50.

[2] Yen et al. (2018) PtdIns(4,5)P₂ stabilises active states of GPCRs and enhances selectivity of G-protein coupling. Nature 559: 423–427.

[3] 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;

[4] 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.

[5] Wang et al. (2020) Lipid interactions of a ciliary membrane TRP channel: simulation and structural studies of polycystin-2. Structure 28: 169-184.