Molecular modeling studies give hint for the existence of a symmetric hβ2R-Gαβγ-homodimer

Abstract

Several experimental studies suggest that GPCR dimers or oligomers may play an important role in signal transduction. In 2011 the crystal structure of a hβ2R-Gαβγ-complex was published and crystal structures of GPCR dimers are known. But until now, no crystal structure of a GPCR dimer including the Gαβγ-complex is available. In order to obtain detailed insights into interactions within hβ2R dimers including the Gαβγ-complex we performed a potential-energy-surface scan in order to identify favored asymmetric and symmetric hβ2R-Gαβγ-homodimers. This potential energy surface scan suggests, besides the existence of asymmetric dimers, the existence of a symmetric hβ2R-Gαβγ-homodimer with a TM I/VII-contact. A subsequent 20 ns MD simulation of the symmetric homodimer revealed large asymmetric conformational changes of both hβ2Rs, especially regarding TM VII and the interaction network between Asp(2.50), Val(7.44), Ser(7.46) and Tyr(7.43). Since similar conformational changes were not observed during the molecular dynamic simulation of the monomeric hβ2R-Gαβγ-complex, it may be suggested that the conformational changes in the symmetric homodimer are related to the presence of the second hβ2R-Gαβγ-complex. Due to the limitations of simulation time, conformational changes within a time scale of μs or ms may of course not be observed. However, the detected conformational changes, especially in TM VII, correspond to minima on the potential energy surface and thus, this study gives new insights into GPCR dimers on molecular level and furthermore, gives suggestions for site-directed mutagenesis studies.