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Ligand binding to the voltage-gated Kv1.5 potassium channel in the open state - Docking and computer simulations of a homology model
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structural Molecular Biology. (Johan Åqvist)
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structural Molecular Biology. (Johan Åqvist)
2008 (English)In: Biophysical Journal, ISSN 0006-3495, Vol. 94, no 3, 820-831 p.Article in journal (Refereed) Published
Abstract [en]

The binding of blockers to the human voltage-gated Kv1.5 potassium ion channel is investigated using a three-step procedure consisting of homology modeling, automated docking, and binding free energy calculations from molecular dynamics simulations, in combination with the linear interaction energy method. A reliable homology model of Kv1.5 is constructed using the recently published crystal structure of the Kv1.2 channel as a template. This model is expected to be significantly more accurate than earlier ones based on less similar templates. Using the three-dimensional homology model, a series of blockers with known affinities are docked into the cavity of the ion channel and their free energies of binding are calculated. The predicted binding free energies are in very good agreement with experimental data and the binding is predicted to be mainly achieved through nonpolar interactions, whereas the relatively small differences in the polar contribution determine the specificity. Apart from confirming the importance of residues V505, I508, V512, and V516 for ligand binding in the cavity, the results also show that A509 and P513 contribute significantly to the nonpolar binding interactions. Furthermore, we find that pharmacophore models based only on optimized free ligand conformations may not necessarily capture the geometric features of ligands bound to the channel cavity. The calculations herein give a detailed structural and energetic picture of blocker binding to Kv1.5 and this model should thus be useful for further ligand design efforts.

Place, publisher, year, edition, pages
2008. Vol. 94, no 3, 820-831 p.
National Category
Biochemistry and Molecular Biology
URN: urn:nbn:se:uu:diva-101410DOI: 10.1529/biophysj.107.112045ISI: 000252243200011PubMedID: 17905851OAI: oai:DiVA.org:uu-101410DiVA: diva2:212963
Available from: 2009-04-26 Created: 2009-04-26 Last updated: 2010-01-15Bibliographically approved
In thesis
1. Computational Analysis of Molecular Recognition Involving the Ribosome and a Voltage Gated K+ Channel
Open this publication in new window or tab >>Computational Analysis of Molecular Recognition Involving the Ribosome and a Voltage Gated K+ Channel
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Over the last few decades, computer simulation techniques have been established as an essential tool for understanding biochemical processes. This thesis deals mainly with the application of free energy calculations to ribosomal complexes and a cardiac ion channel.

The linear interaction energy (LIE) method is used to explore the energetic properties of the essential process of codon–anticodon recognition on the ribosome. The calculations show the structural and energetic consequences and effects of first, second, and third position mismatches in the ribosomal decoding center.

Recognition of stop codons by ribosomal termination complexes is fundamentally different from sense codon recognition. Free energy perturbation simulations are used to study the detailed energetics of stop codon recognition by the bacterial ribosomal release factors RF1 and RF2. The calculations explain the vastly different responses to third codon position A to G substitutions by RF1 and RF2. Also, previously unknown highly specific water interactions are identified.

The GGQ loop of ribosomal RFs is essential for its hydrolytic activity and contains a universally methylated glutamine residue. The structural effect of this methylation is investigated. The results strongly suggest that the methylation has no effect on the intrinsic conformation of the GGQ loop, and, thus, that its sole purpose is to enhance interactions in the ribosomal termination complex.

A first microscopic, atomic level, analysis of blocker binding to the pharmaceutically interesting potassium ion channel Kv1.5 is presented. A previously unknown uniform binding mode is identified, and experimental binding data is accurately reproduced. Furthermore, problems associated with pharmacophore models based on minimized gas phase ligand conformations are highlighted.

Generalized Born and Poisson–Boltzmann continuum models are incorporated into the LIE method to enable implicit treatment of solvent, in an effort to improve speed and convergence. The methods are evaluated and validated using a set of plasmepsin II inhibitors.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 59 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 649
computer simulations, molecular dynamics, ligand binding, binding free energy, linear interaction energy, codon recognition, translation termination, release factor, voltage gated potassium ion channel, Kv1.5
National Category
Structural Biology Biochemistry and Molecular Biology
Research subject
urn:nbn:se:uu:diva-101413 (URN)978-91-554-7539-0 (ISBN)
Public defence
2009-06-12, B41, BMC, Husargatan 3, Uppsala, 13:15 (English)
Available from: 2009-05-20 Created: 2009-04-26 Last updated: 2010-01-13Bibliographically approved

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