Title:Molecular Modeling and Simulation of Membrane Lipid-Mediated Effects on GPCRs
Volume: 20
Issue: 1
Author(s): S.K. Sadiq, R. Guixa-Gonzalez, E. Dainese, M. Pastor, G. De Fabritiis and J. Selent
Affiliation:
Keywords:
G protein-coupled receptor, lipid bilayer, molecular dynamics, hydrophobic mismatch, GPCR regulation, oligomerization, (GPCRs), membrane lipids, complex behavior, computational modeling
Abstract: Functioning of G protein-coupled receptors (GPCRs) is tightly linked to the membrane environment, but a molecular level understanding
of the modulation of GPCR by membrane lipids is not available. However, specific receptor-lipid interactions as well as unspecific
effects mediated by the bulk properties of the membrane (thickness, curvature, etc.) have been proposed to be key regulators of
GPCR modulation. In this review, we examine computational efforts made towards modeling and simulation of (i) the complex behavior
of membrane lipids, (ii) membrane lipid-GPCR interactions as well as membrane lipid-mediated effects on GPCRs and (iii) GPCR oligomerization
in a native-like membrane environment. We propose that, from the perspective of computational modeling, all three of
these components need to be addressed in order to achieve a deeper understanding of GPCR functioning. Presently, we are able to simulate
numerous lipid properties applying advanced computational techniques, although some barriers, such as the time-length of these
simulations, need to be overcome. Implementing three-dimensional structures of GPCRs in such validated membrane systems can give
novel insights in membrane-dependent receptor modulation and formation of higher order receptor complexes. Finally, more realistic
GPCR-membrane models would provide a very useful tool in studying receptor behavior and its modulation by small drug-like ligands, a
relevant issue for drug discovery.
