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Absolute and relative entropies from computer simulation with applications to ligand binding
Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology.
2005 In: Journal of Physical Chemistry B, ISSN 1520-6106, Vol. 109, no 13, 6448-6456 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2005. Vol. 109, no 13, 6448-6456 p.
Identifiers
URN: urn:nbn:se:uu:diva-97215OAI: oai:DiVA.org:uu-97215DiVA: diva2:172049
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

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