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Microsecond Molecular Dynamics Simulations Provide Insight into the Allosteric Mechanism of the Gs Protein Uncoupling from the beta(2) Adrenergic Receptor
KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.ORCID iD: 0000-0001-9035-7086
KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.ORCID iD: 0000-0002-1763-9383
KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.ORCID iD: 0000-0001-8198-9284
2014 (English)In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 118, no 51, 14737-14744 p.Article in journal (Refereed) Published
Abstract [en]

Experiments have revealed that in the beta(2) adrenergic receptor (beta(2)AR)-Gs protein complex the a subunit (G alpha s) of the Gs protein can adopt either an open conformation or a closed conformation. In the open conformation the Gs protein prefers to bind to the beta(2)AR, while in the closed conformation an uncoupling of the Gs protein from the beta(2)AR occurs. However, the mechanism that leads to such different behaviors of the Gs protein remains unclear. Here, we report results from microsecond molecular dynamics simulations and community network analysis of the beta(2)AR-Gs complex with G alpha s in the open and closed conformations. We observed that the complex is stabilized differently in the open and closed conformations. The community network analysis reveals that in the closed conformation there exists strong allosteric communication between the beta(2)AR and G beta gamma, mediated by G alpha s. We suggest that such high information flows are necessary for the Gs protein uncoupling from the beta(2)AR.

Place, publisher, year, edition, pages
2014. Vol. 118, no 51, 14737-14744 p.
Keyword [en]
Coupled Receptors, Crystal-Structure, Structural Basis, Activation Mechanism, Nobel Lecture, Networks, Complex, Mode, Agonists
National Category
Chemical Sciences
URN: urn:nbn:se:kth:diva-159623DOI: 10.1021/jp506579aISI: 000347360100002ScopusID: 2-s2.0-84919933719OAI: diva2:787157
Swedish National Infrastructure for Computing (SNIC), SNIC025/12-38

QC 20150209

Available from: 2015-02-09 Created: 2015-02-05 Last updated: 2015-05-20Bibliographically approved
In thesis
1. Theoretical Studies of G-Protein-Coupled Receptors
Open this publication in new window or tab >>Theoretical Studies of G-Protein-Coupled Receptors
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The family of G-protein-coupled receptors (GPCRs) contains the largest number of drug targets in the human body, with more than a quarter of the clinically used drugs targeting them. Because of the important roles GPCRs play in the human body, the mechanisms of activation of GPCRs or ligands binding to GPCRs have captivated much research interest since the discovery of GPCRs. A number of GPCR crystal structures determined in recent years have provided us with unprecedented opportunities in investigating how GPCRs function through the conformational changes regulated by their ligands. This has motivated me to perform molecular dynamics (MD) simulations in combination with a variety of other modeling methods to study the activation of some GPCRs and their ligand selectivity.

This thesis consists of six chapters. In the first chapter, a brief introduction of GPCRs and MD simulation techniques is given. Detailed MD simulation techniques, including pressure controlling methods and temperature coupling approaches, are described in chapter 2. The metadynamics simulation technique, used to enhance conformational sampling, is described in chapter 3. In chapter 4, I outline the inhomogeneous fluid theory used to calculate the thermodynamics properties of interfacial water molecules. Using the methods described in chapters 2-4, I carried out theoretical investigations on some GPCRs with the results summarized in chapter 5. In chapter 6, I provide a summary of the thesis with future work outlined in an outlook. 

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2015. viii, 60 p.
TRITA-BIO-Report, ISSN 1654-2312 ; 2015:13
National Category
Biological Sciences
Research subject
Biological Physics
urn:nbn:se:kth:diva-166407 (URN)978-91-7595-589-6 (ISBN)
Public defence
2015-06-03, FD5 AlbaNova, Roslagstullsbacken, KTH, Stockholm, 10:00 (English)

QC 201505020

Available from: 2015-05-08 Created: 2015-05-08 Last updated: 2015-05-20Bibliographically approved

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Sun, XianqiangÅgren, HansTu, Yaoquan
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