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

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 μs. 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.