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Continuum solvation models in the linear interaction energy method
Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology.
2006 In: Journal of Physical Chemistry B, ISSN 1520-6106, Vol. 110, no 24, 12034-12041 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2006. Vol. 110, no 24, 12034-12041 p.
Identifiers
URN: urn:nbn:se:uu:diva-97212OAI: oai:DiVA.org:uu-97212DiVA: diva2:172046
Available from: 2008-04-29 Created: 2008-04-29Bibliographically approved
In thesis
1. Challenges in Computational Biochemistry: Solvation and Ligand Binding
Open this publication in new window or tab >>Challenges in Computational Biochemistry: Solvation and Ligand Binding
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Accurate calculations of free energies for molecular association and solvation are important for the understanding of biochemical processes, and are useful in many pharmaceutical applications. In this thesis, molecular dynamics (MD) simulations are used to calculate thermodynamic properties for solvation and ligand binding.

The thermodynamic integration technique is used to calculate pKa values for three aspartic acid residues in two different proteins. MD simulations are carried out in explicit and Generalized-Born continuum solvent. The calculated pKa values are in qualitative agreement with experiment in both cases. A combination of MD simulations and a continuum electrostatics method is applied to examine pKa shifts in wild-type and mutant epoxide hydrolase. The calculated pKa values support a model that can explain some of the pH dependent properties of this enzyme.

Development of the linear interaction energy (LIE) method for calculating solvation and binding free energies is presented. A new model for estimating the electrostatic term in the LIE method is derived and is shown to reproduce experimental free energies of hydration. An LIE method based on a continuum solvent representation is also developed and it is shown to reproduce binding free energies for inhibitors of a malaria enzyme. The possibility of using a combination of docking, MD and the LIE method to predict binding affinities for large datasets of ligands is also investigated. Good agreement with experiment is found for a set of non-nucleoside inhibitors of HIV-1 reverse transcriptase.

Approaches for decomposing solvation and binding free energies into enthalpic and entropic components are also examined. Methods for calculating the translational and rotational binding entropies for a ligand are presented. The possibility to calculate ion hydration free energies and entropies for alkali metal ions by using rigorous free energy techniques is also investigated and the results agree well with experimental data.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 62 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 432
Keyword
Molecular biology, computer simulations, molecular dynamics, solvation free energy, Generalized-Born, Poisson-Boltzmann, ligand binding, binding free energy, linear interaction energy, binding entropy, hydration entropy, Molekylärbiologi
Identifiers
urn:nbn:se:uu:diva-8738 (URN)978-91-554-7200-9 (ISBN)
Public defence
2008-05-23, B7:101, BMC, Husargatan 3, Uppsala, 13:15
Opponent
Supervisors
Available from: 2008-04-29 Created: 2008-04-29Bibliographically approved
2. 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.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 649
Keyword
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
Biochemistry
Identifiers
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)
Opponent
Supervisors
Available from: 2009-05-20 Created: 2009-04-26 Last updated: 2010-01-13Bibliographically approved

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