Journal of Computer-Aided Molecular Design

, Volume 30, Issue 6, pp 489–512 | Cite as

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

  • Fotis A. Baltoumas
  • Margarita C. Theodoropoulou
  • Stavros J. HamodrakasEmail author


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.


G-protein coupled receptors Oligomerization Molecular dynamics Network analysis 



We would like to thank the scientific and administrative staff of the “Bioinformatics” Master’s Program at the Faculty of Biology of the University of Athens, for its generous support. M.C.T. was financially supported as a postdoctoral fellow by Greek State Scholarships Foundation, through the Siemens Program: “IKY Fellowships of Excellence for Postgraduate Studies in Greece – Siemens Program (2014–2015)”. This work was supported by computational time granted from the Greek Research & Technology Network (GRNET) in the National HPC facility—ARIS under project ID “PR001025-M.D.S.B.M.S.”. Finally, we would like to sincerely thank the anonymous reviewers for their very valuable and constructive criticism, which helped us to considerably improve the manuscript, as well as the Editor-in-Chief for properly handling it. The authors declare no conflicts of interest.

Supplementary material

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Supplementary material 1 (PDF 5345 kb)


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Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Fotis A. Baltoumas
    • 1
  • Margarita C. Theodoropoulou
    • 1
    • 2
  • Stavros J. Hamodrakas
    • 1
    Email author
  1. 1.Department of Cell Biology and Biophysics, Faculty of BiologyNational and Kapodistrian University of AthensAthensGreece
  2. 2.Department of Computer Science and Biomedical InformaticsUniversity of Central GreeceLamiaGreece

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