Molecular Modeling and Simulation of Membrane Lipid-Mediated Effects on GPCRs

Functioning of G protein-coupled receptors (GPCRs) is tightly linked to the membrane environment, but a molecular level understandingof the modulation of GPCR by membrane lipids is not available. However, specific receptor-lipid interactions as well as unspecificeffects mediated by the bulk properties of the membrane (thickness, curvature, etc.) have been proposed to be key regulators ofGPCR modulation. In this review, we examine computational efforts made towards modeling and simulation of (i) the complex behaviorof membrane lipids, (ii) membrane lipid-GPCR interactions as well as membrane lipid-mediated effects on GPCRs and (iii) GPCR oligomerizationin a native-like membrane environment. We propose that, from the perspective of computational modeling, all three ofthese components need to be addressed in order to achieve a deeper understanding of GPCR functioning. Presently, we are able to simulatenumerous lipid properties applying advanced computational techniques, although some barriers, such as the time-length of thesesimulations, need to be overcome. Implementing three-dimensional structures of GPCRs in such validated membrane systems can givenovel insights in membrane-dependent receptor modulation and formation of higher order receptor complexes. Finally, more realisticGPCR-membrane models would provide a very useful tool in studying receptor behavior and its modulation by small drug-like ligands, arelevant issue for drug discovery.[...]