Dimerization and domain swapping in G-protein-coupled receptors: A computational study

In recent years there has been an increasing number of reports describing G protein-coupled receptor (GPCR)dimerization and heterodimerization. However, the evidenceon the nature of the dimers and their role in GPCRactivation is inconclusive. Consequently, we present here areview of our computational studies on G protein-coupledreceptor dimerization and domain swapping. The studiesdescribed include molecular dynamics simulations onreceptor monomers and dimers in the absence of ligand, inthe presence of an agonist, and in the presence of anantagonist (or more precisely an inverse agonist). Twodistinct sequence-based approaches to studying proteininterfaces are also described, namely correlated mutationanalysis and evolutionary trace analysis. All threeapproaches concur in supporting the proposal that thedimerization interface includes transmembrane helices 5 and6. These studies cannot distinguish between domainswapped dimers and contact dimers as the models used were restricted to the helical part of the receptor. However, it isproposed that for the purpose of signalling, the domainswapped dimer and the corresponding contact dimer areequivalent. The evolutionary trace analysis suggests thatevery GPCR family and subfamily (for which sufficientsequence data is available) has the potential to dimerizethrough this common functional site on helices 5 and 6. Theevolutionary trace results on the G protein are brieflydescribed and these are consistent with GPCR dimerization.In addition to the functional site on helices 5 and 6, theevolutionary trace analysis identified a second functionalsite on helices 2 and 3. Possible roles for this site aresuggested, including oligomerization.