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Residues remote from the binding pocket control the antagonist selectivity towards the corticotropin-releasing factor receptor-1
KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.ORCID iD: 0000-0001-9035-7086
KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
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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.

Place, publisher, year, edition, pages
2015. Vol. 5, 8066- p.
Keyword [en]
Protein-Coupled Receptors, Beta(2)-Adrenergic Receptor, Molecular-Dynamics, Conformations, Pharmacology, Sensitivity, Activation, Kinetics, Pathway
National Category
Biological Sciences Chemical Sciences
Identifiers
URN: urn:nbn:se:kth:diva-160743DOI: 10.1038/srep08066ISI: 000348435800001PubMedID: 25628267OAI: oai:DiVA.org:kth-160743DiVA: diva2:791887
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
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.
Series
TRITA-BIO-Report, ISSN 1654-2312 ; 2015:13
National Category
Biological Sciences
Research subject
Biological Physics
Identifiers
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)
Opponent
Supervisors
Note

QC 201505020

Available from: 2015-05-08 Created: 2015-05-08 Last updated: 2015-05-20Bibliographically approved
2. Computational Studies of Structures and Binding Properties of Protein-Ligand Complexes
Open this publication in new window or tab >>Computational Studies of Structures and Binding Properties of Protein-Ligand Complexes
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Proteins are dynamic structural entities that are involved in many biophysical processes through molecular interactions with their ligands. Protein-ligand interactions are of fundamental importance for computer-aided drug discovery. Due to the fast development in computer technologies and theoretical methods, computational studies are by now able to provide atomistic-level description of structures, thermodynamic and dynamic properties of protein-ligand systems, and are becoming indispensable in understanding complicated biomolecular systems. In this dissertation, I have applied molecular dynamic (MD) simulations combined with several state of the art free-energy calculation methodologies, to understand structures and binding properties of several protein-ligand systems.

The dissertation consists of six chapters. In the first chapter, I present a brief introduction to classical MD simulations, to recently developed methods for binding free energy calculations, and to enhanced sampling of configuration space of biological systems. The basic features, including the Hamiltonian equations, force fields, integrators, thermostats, and barostats, that contribute to a complete MD simulation are described in chapter 2. In chapter 3, two classes of commonly used algorithms for estimating binding free energies are presented. I highlight enhanced sampling approaches in chapter 4, with a special focus on replica exchange MD simulations and metadynamics, as both of them have been utilized in my work presented in the chapter thereafter. In chapter 5, I outlined the work in the 5 papers included in the thesis. In paper I and II, I applied, respectively, the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) and alchemical free energy calculation methods to identify the molecular determinant of the affibody protein ZAb3 bound to an amyloid b peptide, and to investigate the binding profile of the positive allosteric modulator NS-1738 with the α7 acetylcholine-binding protein (α7-AChBP protein); in paper III and VI, unbiased MD simulations were integrated with the well-tempered metadynamics approach, with the aim to reveal the mechanism behind the higher selectivity of an antagonist towards corticotropin-releasing factor receptor-1 (CRF1R) than towards CRF2R, and to understand how the allosteric modulation induced by a sodium ion is propagated to the intracellular side of the d-opioid receptor; in the last paper, I proved the structural heterogeneity of the intrinsically disordered AICD peptide, and then employed the bias-exchange metadynamics and kinetic Monte Carlo techniques to understand the coupled folding and binding of AICD to its receptor Fe65-PTB2. I finally proposed that the interactions between AICD and Fe65-PTB2 take place through an induced-fit mechanism. In chapter 6, I made a short conclusion of the work, with an outlook of computational simulations of biomolecular systems.

Place, publisher, year, edition, pages
Stockholm, Sweden: KTH Royal Institute of Technology, 2017. 73 p.
Series
TRITA-BIO-Report, ISSN 1654-2312 ; 2017:13
National Category
Theoretical Chemistry
Research subject
Theoretical Chemistry and Biology
Identifiers
urn:nbn:se:kth:diva-207100 (URN)978-91-7729-421-4 (ISBN)
Public defence
2017-06-02, FB52, AlbaNova University Center, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

QC 20170516

Available from: 2017-05-16 Created: 2017-05-15 Last updated: 2017-05-16Bibliographically approved

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