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

Freddie Salsbury Jr,Huanxiang Liu,Yihe Ban,Yang Zhang,Xiaojun Yao,Qifeng Bai

doi:10.1371/journal.pone.0068138

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.

Highlights

The b2 adrenergic receptor (b2AR) belonged to class A G protein-coupled receptors (GPCRs) [1] and regulated many key physiologically processes such as smooth muscle relaxation in the airways and the vasculature [2,3,4,5,6,7]
The loop between TM5 and TM6 was modeled on basis of the crystal structure of b2 adrenergic receptor-Gs (b2AR-Gs)
The 200 ns molecular dynamics (MD) simulations were performed for b2AR-Gs in complex with different ligands on a workstation equipped with four pieces of graphics processing unit (GPU) and two processors with six cores

Summary

Introduction

The b2 adrenergic receptor (b2AR) belonged to class A G protein-coupled receptors (GPCRs) [1] and regulated many key physiologically processes such as smooth muscle relaxation in the airways and the vasculature [2,3,4,5,6,7]. The crystal structure of b2AR in complex with the inverse agonist carazolol was determined in 2007 It revealed the inactive conformation of b2AR [8]. This work gave a model system for understanding the detailed mechanism about the activation of Gs and for understanding the ligands induced conformation change of b2 adrenergic receptor-Gs (b2AR-Gs) protein complex [12]. Engineering and characterization of b2AR-based on ion-channel coupled receptors gave new insights into the conformational dynamics of b2AR [14]. All these studies indicated that it was difficult to obtain the crystal structure of the agonist-bound to active conformation of b2AR if the G protein did not bind to b2AR

Methods

Results

Conclusion