G Protein-Coupled Receptors Self-Assemble in Dynamics Simulations of Model Bilayers

Abstract

Many integral membrane proteins assemble to form oligomeric structures in biological membranes. In particular, seven-transmembrane helical G protein-coupled receptors (GPCRs) appear to self-assemble constitutively in membranes, but the mechanism and physiological role of this assembly are unknown. We developed and employed coarse-grain molecular dynamics (CGMD) models to investigate the molecular basis of how the physicochemical properties of the phospholipid bilayer membrane affect self-assembly of visual rhodopsin, a prototypical GPCR. The CGMD method is a mesoscopic simulation technique in which groups of atoms are mapped to particles on the basis of a four-to-one rule. This systematic reduction of the degrees of freedom allows for computationally efficient calculation of the structure and dynamics of molecular assemblies for larger time and length scales than accessible to atomistic models, providing here an unprecedented view of spontaneous protein assembly in biomembranes. Systems with up to 16 rhodopsin molecules at a protein-to-lipid ratio of 1:100 were simulated for time scales of up to 8 micros. The results obtained for four different phospholipid environments showed that localized adaptation of the membrane bilayer to the presence of receptors is reproducibly most pronounced near transmembrane helices 2, 4, and 7. This local membrane deformation appears to be a key factor defining the rate, extent, and orientational preference of protein-protein association. The implications of our findings are discussed within a framework of a generalized mechanism of membrane protein self-assembly.

Bilayer-thickness-mediated interactions between integral membrane proteins

“…The directionality of bilayer thickness-mediated protein interactions implied by the observed protein structures presents one possible physical mechanism for membrane protein organization and collective function. Such directional interactions can yield [46,47,89,97] ordering of integral membrane proteins, which is also consistent with molecular dynamics simulations [84,95,125,126]. The combined analytic and numerical framework we have discussed here allows calculation of the lipid bilayer-mediated protein interactions implied by bilayer elasticity theory [32][33][34][35][36][37][38][39][40][41][42][43] for the protein shapes suggested by structural studies at arbitrary protein separations and orientations.…”

G protein-coupled receptor-receptor interactions give integrative dynamics to intercellular communication

“…Consequently, if the protein's hydrophobic part exceeds the bilayer thickness, oligomerization might reduce the exposed hydrophobic area of the protein (Killian, 1998). Using computational methods, this process was analyzed with reference to the association of rhodopsin (Periole et al, 2007) and of the β 1 -and β 2 -adrenergic receptors (Mondal et al, 2013). Interestingly, it was observed that the protein domains most frequently involved in RRIs were also those showing the highest hydrophobic mismatch in monomers, which was substantially alleviated in oligomers.…”

Dimerization of visual pigments in vivo

“…6B, Top and Middle Rows). Thus, the H1/H8 domains rather than the H4/H5 domains may be the primary protomer-protomer interface in R/R-opsin and R/S-opsin dimerization during biosynthesis and targeting, although secondary interactions in the H4/H5 domains and even others are still possible in the ROS (33)(34)(35)(36). This result is consistent with the cross-linking experiment involving BM(PEG) 3 and MTS-O5-MTS, whose extended S-S distance of 2.1 and 2.6 nm, respectively, is within the predicted C316-C316 distance of 2.1-2.9 nm in the rhodopsin H1/H8 dimer (2.4 nm in the R/S-opsin heterodimer) (Fig.…”