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Theoretical Studies of G-Protein-Coupled Receptors
KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.ORCID iD: 0000-0001-9035-7086
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.
Series
TRITA-BIO-Report, ISSN 1654-2312 ; 2015:13
National Category
Biological Sciences
Research subject
Biological Physics
Identifiers
URN: urn:nbn:se:kth:diva-166407ISBN: 978-91-7595-589-6 (print)OAI: oai:DiVA.org:kth-166407DiVA: diva2:810907
Public defence
2015-06-03, FD5 AlbaNova, Roslagstullsbacken, KTH, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

QC 201505020

Available from: 2015-05-08 Created: 2015-05-08 Last updated: 2015-05-20Bibliographically approved
List of papers
1. Functional Water Molecules in Rhodopsin Activation
Open this publication in new window or tab >>Functional Water Molecules in Rhodopsin Activation
2014 (English)In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 118, no 37, 10863-10873 p.Article in journal (Refereed) Published
Abstract [en]

G-protein-coupled receptors (GPCRs) are integral membrane proteins that mediate cellular response to an extensive variety of extracellular stimuli. Studies of rhodopsin, a prototype GPCR, have suggested that water plays an important role in mediating the activation of family A GPCRs. However, our understanding of the function of water molecules in the GPCR activation is still rather limited because resolving the functional water molecules solely based on the results from existing experiments is challenging. Using all-atom molecular dynamics simulations in combination with inhomogeneous fluid theory, we identify in this work the positioning of functional water molecules in the inactive state, the Meta II state, and the constitutive active state of rhodopsin, basing on the thermodynamic signatures of the water molecules. We find that one hydration site likely functions as a switch to regulate the distance between Glu181 and the Schiff base in the rhodopsin activation. We observe that water molecules adjacent to the "NpxxY" motif are not as stable in the Meta II state as in the inactive state as indicated by the thermodynamics signatures, and we rationalize that the behaviors of these water molecules are closely correlated with the rearrangement of the water-mediated hydrogen-bond network in the "NPxxY" motif, which is essential for mediating the activation of the receptor. We thereby propose a hypothesis of the water-mediated rhodopsin activation pathway.

Keyword
Protein-Coupled-Receptors, Ligand-Binding, Metarhodopsin-Ii, Squid Rhodopsin, Dynamics, Light, Thermodynamics, Chromophore, Photoactivation, Crystallography
National Category
Physical Chemistry
Identifiers
urn:nbn:se:kth:diva-154376 (URN)10.1021/jp505180t (DOI)000342120100006 ()2-s2.0-84926443535 (Scopus ID)
Note

QC 20141021

Available from: 2014-10-21 Created: 2014-10-20 Last updated: 2017-12-05Bibliographically approved
2. Function of the sodium ion in the activation of the δ-Opioid receptor
Open this publication in new window or tab >>Function of the sodium ion in the activation of the δ-Opioid receptor
(English)Manuscript (preprint) (Other academic)
National Category
Biological Sciences
Research subject
Biological Physics
Identifiers
urn:nbn:se:kth:diva-166406 (URN)
Note

QS 2015

Available from: 2015-05-08 Created: 2015-05-08 Last updated: 2015-05-20Bibliographically approved
3. Microsecond Molecular Dynamics Simulations Provide Insight into the Allosteric Mechanism of the Gs Protein Uncoupling from the beta(2) Adrenergic Receptor
Open this publication in new window or tab >>Microsecond Molecular Dynamics Simulations Provide Insight into the Allosteric Mechanism of the Gs Protein Uncoupling from the beta(2) Adrenergic Receptor
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.

Keyword
Coupled Receptors, Crystal-Structure, Structural Basis, Activation Mechanism, Nobel Lecture, Networks, Complex, Mode, Agonists
National Category
Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-159623 (URN)10.1021/jp506579a (DOI)000347360100002 ()2-s2.0-84919933719 (Scopus ID)
Funder
Swedish National Infrastructure for Computing (SNIC), SNIC025/12-38
Note

QC 20150209

Available from: 2015-02-09 Created: 2015-02-05 Last updated: 2017-12-04Bibliographically approved
4. Residues remote from the binding pocket control the antagonist selectivity towards the corticotropin-releasing factor receptor-1
Open this publication in new window or tab >>Residues remote from the binding pocket control the antagonist selectivity towards the corticotropin-releasing factor receptor-1
Show others...
2015 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, 8066- p.Article in journal (Refereed) Published
Abstract [en]

The corticotropin releasing factors receptor-1 and receptor-2 (CRF1R and CRF2R) are therapeutic targets for treating neurological diseases. Antagonists targeting CRF1R have been developed for the potential treatment of anxiety disorders and alcohol addiction. It has been found that antagonists targeting CRF1R always show high selectivity, although CRF1R and CRF2R share a very high rate of sequence identity. This has inspired us to study the origin of the selectivity of the antagonists. We have therefore built a homology model for CRF2R and carried out unbiased molecular dynamics and well-tempered metadynamics simulations for systems with the antagonist CP-376395 in CRF1R or CRF2R to address this issue. We found that the side chain of Tyr(6.63) forms a hydrogen bond with the residue remote from the binding pocket, which allows Tyr(6.63) to adopt different conformations in the two receptors and results in the presence or absence of a bottleneck controlling the antagonist binding to or dissociation from the receptors. The rotameric switch of the side chain of Tyr356(6.63) allows the breaking down of the bottleneck and is a perquisite for the dissociation of CP-376395 from CRF1R.

Keyword
Protein-Coupled Receptors, Beta(2)-Adrenergic Receptor, Molecular-Dynamics, Conformations, Pharmacology, Sensitivity, Activation, Kinetics, Pathway
National Category
Biological Sciences Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-160743 (URN)10.1038/srep08066 (DOI)000348435800001 ()25628267 (PubMedID)
Funder
Swedish National Infrastructure for Computing (SNIC), SNIC2013-26-31 SNIC2013-1-236
Note

QC 20150302

Available from: 2015-03-02 Created: 2015-02-27 Last updated: 2017-12-04Bibliographically approved

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