Molecular dynamics simulations and structure-based network analysis reveal structural and functional aspects of G-protein coupled receptor dimer interactions

• Published in: Journal of computer-aided molecular design 2016-06, Vol.30 (6), p.489-512
• Main Authors: Baltoumas, Fotis A., Theodoropoulou, Margarita C., Hamodrakas, Stavros J.
• Format: Article
• Language: English
• Subjects: Animal Anatomy; Chemistry; Chemistry and Materials Science; Computer Applications in Chemistry; Computer simulation; Determinants; Dimers; Dynamics; Histology; Humans; Models, Molecular; Molecular biology; Molecular dynamics; Molecular Dynamics Simulation; Morphology; Network operating systems; Networks; Neurons; Oligomerization; Physical Chemistry; Proteins; Receptors; Receptors, G-Protein-Coupled - chemistry; Receptors, G-Protein-Coupled - metabolism; Simulation; Structure-Activity Relationship; Systems analysis
• ISSN: 0920-654X; 1573-4951
• DOI: 10.1007/s10822-016-9919-y

A significant amount of experimental evidence suggests that G-protein coupled receptors (GPCRs) do not act exclusively as monomers but also form biologically relevant dimers and oligomers. However, the structural determinants, stoichiometry and functional importance of GPCR oligomerization remain topics of intense speculation. In this study we attempted to evaluate the nature and dynamics of GPCR oligomeric interactions. A representative set of GPCR homodimers were studied through Coarse-Grained Molecular Dynamics simulations, combined with interface analysis and concepts from network theory for the construction and analysis of dynamic structural networks. Our results highlight important structural determinants that seem to govern receptor dimer interactions. A conserved dynamic behavior was observed among different GPCRs, including receptors belonging in different GPCR classes. Specific GPCR regions were highlighted as the core of the interfaces. Finally, correlations of motion were observed between parts of the dimer interface and GPCR segments participating in ligand binding and receptor activation, suggesting the existence of mechanisms through which dimer formation may affect GPCR function. The results of this study can be used to drive experiments aimed at exploring GPCR oligomerization, as well as in the study of transmembrane protein–protein interactions in general.