Computational Study on the Different Ligands Induced Conformation Change of β2 Adrenergic Receptor-Gs Protein Complex

Abstract

β2 adrenergic receptor (β2AR) regulated many key physiological processes by activation of a heterotrimeric GTP binding protein (Gs protein). This process could be modulated by different types of ligands. But the details about this modulation process were still not depicted. Here, we performed molecular dynamics (MD) simulations on the structures of β2AR-Gs protein in complex with different types of ligands. The simulation results demonstrated that the agonist BI-167107 could form hydrogen bonds with Ser2035.42, Ser2075.46 and Asn2936.55 more than the inverse agonist ICI 118,551. The different binding modes of ligands further affected the conformation of β2AR. The energy landscape profiled the energy contour map of the stable and dissociated conformation of Gαs and Gβγ when different types of ligands bound to β2AR. It also showed the minimum energy pathway about the conformational change of Gαs and Gβγ along the reaction coordinates. By using interactive essential dynamics analysis, we found that Gαs and Gβγ domain of Gs protein had the tendency to separate when the inverse agonist ICI 118,551 bound to β2AR. The α5-helix had a relatively quick movement with respect to transmembrane segments of β2AR when the inverse agonist ICI 118,551 bound to β2AR. Besides, the analysis of the centroid distance of Gαs and Gβγ showed that the Gαs was separated from Gβγ during the MD simulations. Our results not only could provide details about the different types of ligands that induced conformational change of β2AR and Gs protein, but also supplied more information for different efficacies of drug design of β2AR.

A Systematic Review of Inverse Agonism at Adrenoceptor Subtypes

“…NMR spectroscopy has been reported to map three [ 142 ], and molecular dynamic simulations to map seven receptor activation states to different energy states [ 143 ]. Some ligands (‘true’ neutral antagonists) do not appear to shift the receptor activity level set by specific assay conditions [ 144 ]. Different types of ligands (agonists, antagonists, and inverse agonists) modulated the conformational dynamics differently [ 145 ].…”

Mechanistic Insights into Specific G Protein Interactions with Adenosine Receptors Revealed by Accelerated Molecular Simulations

“…[15][16][17] MD simulations have shown that conformational dynamics of the GPCR-G protein complex depends on the bound ligands. 18,19 Moreover, MD simulations have suggested that the binding of the active GPCR is necessary for nucleotide release from the G protein. [20][21][22][23] However, due to limited timescales, conventional MD (cMD) simulations often suffer from insufficient sampling, precluding proper free energy calculations to characterize GPCR-G protein interactions quantitatively.…”

Agonist binding by the β2-adrenergic receptor: an effect of receptor conformation on ligand association–dissociation characteristics

“…The interactions between β 2 -AR and ligands, and the mechanism of receptor activation have been intensively studied (Bai et al 2013 ; Cherezov et al 2007 ; Rasmussen et al 2011a , b ; Ring et al 2013 ; Staus et al 2014 ; Kim et al 2013 ; Zocher et al 2012 ; Deupi et al 2012 ; Yao et al 2006 ). Analysis of the ligand-binding region of β 2 -AR on the basis of recently solved high-resolution crystal structures revealed several highly conserved amino acids that might be involved in ligand binding.…”