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Functional Water Molecules in Rhodopsin Activation
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 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.

Place, publisher, year, edition, pages
2014. Vol. 118, no 37, 10863-10873 p.
Keyword [en]
Protein-Coupled-Receptors, Ligand-Binding, Metarhodopsin-Ii, Squid Rhodopsin, Dynamics, Light, Thermodynamics, Chromophore, Photoactivation, Crystallography
National Category
Physical Chemistry
URN: urn:nbn:se:kth:diva-154376DOI: 10.1021/jp505180tISI: 000342120100006ScopusID: 2-s2.0-84926443535OAI: diva2:757186

QC 20141021

Available from: 2014-10-21 Created: 2014-10-20 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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