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Understanding the effects on constitutive activation and drug binding of a D130N mutation in the β2 adrenergic receptor via molecular dynamics simulation

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Abstract

G-protein-coupled receptors (GPCRs) are currently one of the largest families of drug targets. The constitutive activation induced by mutation of key GPCR residues is associated closely with various diseases. However, the structural basis underlying such activation and its role in drug binding has remained unclear. Herein, we used all-atom molecular dynamics simulations and free energy calculations to study the effects of a D130N mutation on the structure of β2 adrenergic receptor (β2AR) and its binding of the agonist salbutamol. The results indicate that the mutation caused significant changes in some key helices. In particular, the mutation leads to the departure of transmembrane 3 (TM3) from transmembrane 6 (TM6) and marked changes in the NPxxY region as well as the complete disruption of a key ionic lock, all of which contribute to the observed constitutive activation. In addition, the D130N mutation weakens some important H-bonds, leading to structural changes in these regions. Binding free energy calculations indicate that van der Waals and electrostatic interactions are the main driving forces in binding salbutamol; however, binding strength in the mutant β2AR is significantly enhanced mainly through modifying electrostatic interactions. Further analysis revealed that the increase in binding energy upon mutation stems mainly from the H-bonds formed between the hydroxyl group of salbutamol and the serine residues of TM5. This observation suggests that modifications of the H-bond groups of this drug could significantly influence drug efficacy in the treatment of diseases associated with this mutation.

All-atom molecular dynamics simulation and free energy calculations were used to study the effects of the D130N mutation on the structure of β2 adrenergic receptor (β2AR) and its binding with salbutamol agonist. The results indicate that the mutation induces significant changes in some important regions and favors agonist binding mainly through increasing non-bond electrostatic interactions

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Acknowledgment

This project was supported by the National Science Foundation of China (Grant No. 21273154, U1230121).

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Authors and Affiliations

  1. Faculty of Chemistry, Sichuan University, No. 29 Jiuyanqiao Wangjiang Road, Chengdu, 610064, People’s Republic of China

    Yanyan Zhu, Xiuchan Xiao, Liyun Zhang, Yanzhi Guo & Xuemei Pu

  2. College of Management, Southwest University for Nationalities, Chengdu, 610041, People’s Republic of China

    Yuan Yuan

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  1. Yanyan Zhu
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  2. Yuan Yuan
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Correspondence to Xuemei Pu.

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Zhu, Y., Yuan, Y., Xiao, X. et al. Understanding the effects on constitutive activation and drug binding of a D130N mutation in the β2 adrenergic receptor via molecular dynamics simulation. J Mol Model 20, 2491 (2014). https://doi.org/10.1007/s00894-014-2491-2

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