Available online at www.sciencedirect.com Bioinformatics and molecular modelling approaches to GPCR oligomerization Lisa M Simpson 1 , Bruck Taddese 1 , Ian D Wall 2 and Christopher A Reynolds 1 The elusive nature of the structure and function of the G-protein coupled receptor (GPCR) dimer or oligomer has led to a variety of computational studies, most of which have been directed primarily towards understanding structure. Here we review some of the recent studies based on sequence analysis and docking experiments and the recent developments in GPCR structure that have underpinned dimerization studies. In addition, we review recent nanosecond molecular dynamics simulations and coarse-grained methods for investigating the dynamic consequences of dimerization. The strengths and weaknesses of these complementary methods are discussed. The consensus of a variety of studies is that several transmembrane helices are involved in the dimerization/ oligomerization interface(s); computation has been particularly effective in elucidating the experiments that seem to indicate a key role for transmembrane helix 4. Addresses 1 Department of Biological Sciences, University of Essex, Wivenhoe Park, Colchester CO4 3SQ, United Kingdom 2 GlaxoSmithKline, Third Avenue, Harlow, Essex CM19 5AW, United Kingdom Corresponding author: Reynolds, Christopher A (reync@essex.ac.uk) Current Opinion in Pharmacology 2010, 10:30–37 This review comes from a themed issue on GPCR Edited by Rafael Franco and Sergi Ferre ´ 1471-4892/$ – see front matter # 2009 Elsevier Ltd. All rights reserved. DOI 10.1016/j.coph.2009.11.001 Introduction G-protein coupled receptor (GPCR) oligomerization has been an area of interest and controversy for many years. Recently there has been increasing evidence that both homo-dimers and hetero-dimers play a crucial role in GPCR signalling. Whilst the modelling of these oligo- mers remains a specialist area, it is important to review recent progress in this area, to review the work that has laid the foundations for these advances and to reinforce the expectation that theoretical methods will play an increasingly important role in the future. The earliest computational treatments of GPCR dimerization were highly controversial [1–5], primarily because of their embryonic nature. Current work is far less limited by the availability of sequence, structural and other biological data, and by limitations in computational methods and resources. Nevertheless, the power of com- putation per se is indicated by the way many of the earlier predictions have been justified by subsequent exper- iment, as discussed by Vohra et al. [6  ]. Here we outline some of the more recent computational studies that have greatly enhanced our understanding of GPCR dimeriza- tion through prediction and through commentary on relevant experiments. A new GPCR dimer database Surprisingly, one of the best recent reviews on GPCR dimerization is contained in an article on a new GPCR oligomerization database [7  ] (URL: www.gpcr-okb.org). The article is highly interesting as it embraces both experiment and theory on an equal footing. The database defines some of the key concepts in GPCR oligomeriza- tion such as physiological relevance, through the use of relevant ‘attributes’, some of which are given in Table 1. By seeking to specify the database information scheme as fully as possible and by using well-chosen examples to illustrate it, the article makes an excellent review of the current understanding of GPCR dimerization. These examples include, the different effects of first, agonists, partial agonists and antagonists on the BRET signal in CCK; second, different optimal binding site occupancies; third, discussions of asymmetry and trans-activation and fourth, the stoichiometry of the signalling complex. The article thus highlights key controversial issues such as the location of the dimerization interface, the identity of the interacting residues, the optimal ligand occupancy (e.g. one ligand per dimer) and the nature of the conformation- al change. Given that different GPCR oligomeric systems appear to show different behaviour under experimental challenge, the overall interpretation can sometimes be unclear. Thus, whilst the database does permit the reports of interpretations, for example through the deducedFrom- Studies ‘attribute’, the key aim is to record the basic facts. Currently the database exists as a concept since the information scheme has been defined, but the database has not yet been populated with data [7  ]. Mechanisms for uploading data to the database are discussed and if this concept becomes a reality it will be extremely useful. Although we note that some dimerization information is currently available in the gpDB database (URL: http:// bioinformatics.biol.uoa.gr/gpDB)[8], we consider the introduction of a resource dedicated specifically to oligo- merization studies to be a valuable addition and encou- rage its development into a fully working database. Current Opinion in Pharmacology 2010, 10:30–37 www.sciencedirect.com