In silico analysis of the binding of agonists and blockers to the β2-adrenergic receptor

Activation of G protein-coupled receptors (GPCRs) is a complex phenomenon. Here, we applied Induced Fit Docking (IFD) in tandem with linear discriminant analysis (LDA) to generate hypotheses on the conformational changes induced to the β2-adrenergic receptor by agonist binding, preliminary to the sequence of events that characterize activation of the receptor. This analysis, corroborated by a follow-up molecular dynamics study, suggested that agonists induce subtle movements to the fifth transmembrane domain (TM5) of the receptor. Furthermore, molecular dynamics also highlighted a correlation between movements of TM5 and the second extracellular loop (EL2), suggesting that freedom of motion of EL2 is required for the agonist-induced TM5 displacement. Importantly, we also showed that the IFD/LDA procedure can be used as a computational means to distinguish agonists from blockers on the basis of the differential conformational changes induced to the receptor. In particular, the two most predictive models obtained are based on the RMSD induced to Ser207 and on the counterclockwise rotation induced to TM5.

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► Applied Induced Fit Docking (IFD) and discriminant analysis (LDA) to study agonist binding.
► Performed follow-up molecular dynamics in a hydrated lipid bilayer model.
► Agonists were found to subtly displace the fifth transmembrane domain (TM5) of the receptor.
► Correlation was found between movements of TM5 and second extracellular loop (EL2).
► IFD/LDA showed the potential to be also used as a tool to distinguish agonists from blockers.