Interactions with specific lipids are important in the function and stability of membrane proteins. Multi-scale molecular dynamics simulations enable exploration of structural, energetic, and dynamic aspects of these interactions. We have used an approach based on coarse-grained (CG) simulations in mixed lipid bilayers to identify potential lipid interaction sites. These predicted interactions are then probed further by estimation of CG free energy landscapes of protein/lipid interactions to determine lipid specificity, and by atomistic MD simulations to refine models of the structure and dynamics of lipid binding. This approach has been applied to a number of GPCRs and ion channels. Analysis of lipid interactions with Class A GPCRs (e.g. the A2a receptor) has revealed binding sites for GM3, cholesterol, and PIP2. 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 of the receptor. PIP2 also plays a role in strengthening GPCR/G protein interactions [1,2]. Interactions of lipids with other classes of GPCRs have been explored, including the interactions of cholesterol and PIP2 with Smoothened [3]. Analysis of the interactions of lipids with ion channels has focussed on PIP2, a known 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 may modulate channel-channel interactions within crowded membranes [4].

Membrane protein interactions with lipids: GPCRs and ion channels

2019 Spring National Meeting

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