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Characterization of the binding mode of the PET tracer [18F]ASEM to a chimera structure of the α7 nicotinic acetylcholine receptor
KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
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2017 (English)In: RSC Advances, ISSN 2046-2069, E-ISSN 2046-2069, Vol. 7, no 32, p. 19787-19793Article in journal (Refereed) Published
Abstract [en]

The α7 nicotinic acetylcholine receptor (α7-nAChR) is assumed to be implicated in a variety of neurological disorders, such as schizophrenia and Alzheimer's disease (AD). The progress of these disorders can be studied through imaging α7-nAChR with positron emission tomography (PET). [18F]ASEM is a novel and potent α7-nAChR PET radioligand showing great promise in recent tests. However, the mechanism of the molecular interaction between [18F]ASEM and α7-nAChR is still unclear. In this paper, the binding profile of [18F]ASEM to a chimera structure of α7-nAChR was investigated with molecular docking, molecular dynamics, and metadynamics simulation methods. We found that [18F]ASEM binds at the same site as the crystallized agonist epibatidine but with a different binding mode. The dibenzo[b,d]thiophene ring has a different orientation compared to the pyridine ring of epibatidine and has van der Waals interactions with residues from loop C on one side and π-π stacking interaction with Trp53 on the other side. The conformation of Trp53 was found to have a great impact on the binding of [18F]ASEM. Six binding modes in terms of the side chain dihedral angles χ1 and χ2 of Trp53 were discovered by metadynamics simulation. In the most stable binding mode, Trp53 adopts a different conformation from that in the crystalline structure and has a rather favorable π-π stacking interaction with [18F]ASEM. We believe that these discoveries can be valuable for the development of novel PET radioligands.

Place, publisher, year, edition, pages
Royal Society of Chemistry , 2017. Vol. 7, no 32, p. 19787-19793
Keywords [en]
Binding energy, Dihedral angle, Molecular dynamics, Neurodegenerative diseases, Positron emission tomography, Van der Waals forces, Alzheimer's disease, Crystalline structure, Metadynamics simulations, Molecular docking, Neurological disorders, Nicotinic acetylcholine receptors, Positron emission tomography (PET), Van Der Waals interactions, Bins
National Category
Chemical Sciences
Identifiers
URN: urn:nbn:se:kth:diva-207402DOI: 10.1039/c7ra00496fISI: 000399242100041Scopus ID: 2-s2.0-85017176981OAI: oai:DiVA.org:kth-207402DiVA, id: diva2:1104654
Funder
Swedish Foundation for Strategic Research , RB13-0192Stockholm County Council, K1764-2013Swedish National Infrastructure for Computing (SNIC), m.2015-1-396
Note

Funding details: CSC, China Scholarship Council; Funding text: The authors acknowledge support from the Swedish Foundation for Strategic Research (SSF) through the project “New imaging biomarkers in early diagnosis and treatment of Alzheimer's disease (RB13-0192)” and the support from the Stockholm Country Council through the project “Biomolecular profiling for early diagnosis of Alzheimer's disease (K1764-2013)”. Computer time for this work was awarded by a grant from the Swedish Infrastructure Committee (SNIC) for the project “Modeling of protein-ligand binding” (m.2015-1-396). The figures containing molecular structures were rendered with PyMol 1.3 (ref. 51) and VMD 1.9.2 (ref. 52). The work was partly sponsored by the China Scholarship Council (CSC).

QC 20170601

Available from: 2017-06-01 Created: 2017-06-01 Last updated: 2019-05-10Bibliographically approved
In thesis
1. Computational Studies of Protein-ligand Systems Using Enhanced Sampling Methods
Open this publication in new window or tab >>Computational Studies of Protein-ligand Systems Using Enhanced Sampling Methods
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis focuses on studies of protein-ligand systems using enhanced sampling methods. In chapter I, I give a brief introduction to the time-scale problem and some enhanced sampling methods. In chapter II, the basics of MD simulation are reviewed. In chapter III, the theoretical backgrounds of umbrella sampling, bias-exchange metadynamics and infrequent metadynamics are presented. In chapter IV, the 5 papers included in this thesis are summarized. In paper 1, we studied the relationship between the antibacterial activities of antimicrobial peptides and their aggregation propensities. We found that an increasing aggregation propensity increases the free energy cost of peptide embedding into the bacterial membrane and decreases antibacterial activity. In paper 2, we employed the umbrella sampling approach to obtain the free energy landscape of Pittsburgh compound-B penetrating into the core binding sites of amyloid βfibrils. Our study suggested that, for the design of probes binding to fibril like proteins, other than the binding affinity, the dynamics of probes in the fibrils should also be considered. In paper 3, we studied the coupled folding and binding process of the intrinsically disordered protein p53 to MDM2 with bias-exchange metadynamics and infrequent metadynamics. We reconstructed the free energy landscape and built a kinetic network for this process. In paper 4, we studied the binding modes of ASEM with a chimera structure of α7 nicotinic acetylcholine receptor with well-tempered metadynamics. We found that an important residue, Trp53, can significantly affect the stabilities of the binding modes. In paper 5, we proposed an efficient method to estimate the transition times of rare events in biomolecular systems. In chapter V, I present a conclusion of this thesis and propose an outlook related to the selection of collective variables for enhanced sampling methods.

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2019. p. 58
Series
TRITA-CBH-FOU ; 34
Keywords
molecular dynamics, enhanced sampling, protein-ligand interactions, umbrella sampling, metadynamics
National Category
Natural Sciences
Research subject
Theoretical Chemistry and Biology
Identifiers
urn:nbn:se:kth:diva-251025 (URN)
Public defence
2019-06-05, FP41, Roslagstullsbacken 33, Byggnad 1, floor 4, AlbaNova, Stockholm, 10:00 (English)
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Note

QC 2019-05-10

Available from: 2019-05-10 Created: 2019-05-08 Last updated: 2019-05-10Bibliographically approved

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