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Challenges in Computational Biochemistry: Solvation and Ligand Binding
Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Cell and Molecular Biology.
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. , p. 62
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 432
Keywords [en]
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
Keywords [sv]
Molekylärbiologi
Identifiers
URN: urn:nbn:se:uu:diva-8738ISBN: 978-91-554-7200-9 (print)OAI: oai:DiVA.org:uu-8738DiVA, id: diva2:172052
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
List of papers
1. Proton binding to proteins: pKa calculations with explicit and implicit solvent models
Open this publication in new window or tab >>Proton binding to proteins: pKa calculations with explicit and implicit solvent models
2004 In: Journal of the American Chemical Society, ISSN 0002-7863, Vol. 126, no 13, p. 4167-4180Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-97210 (URN)
Available from: 2008-04-29 Created: 2008-04-29Bibliographically approved
2. Active site of epoxide hydrolases revisited: A noncanonical residue in potato StEH1 promotes both formation and breakdown of the alkylenzyme intermediate
Open this publication in new window or tab >>Active site of epoxide hydrolases revisited: A noncanonical residue in potato StEH1 promotes both formation and breakdown of the alkylenzyme intermediate
2007 (English)In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 46, no 9, p. 2466-2479Article in journal (Refereed) Published
Abstract [en]

The carboxylate of Glu(35) in the active site of potato epoxide hydrolase StEH1 interacts with the catalytic water molecule and is the first link in a chain of hydrogen bonds connecting the active site with bulk solvent. To probe its importance to catalysis, the carboxylate was replaced with an amide through an E35Q mutation. Comparing enzyme activities using the two trans-stilbene oxide (TSO) enantiomers as substrates revealed the reaction with R,R-TSO to be the one more severely affected by the E35Q mutation, as judged by determined kinetic parameters describing the pre-steady states or the steady states of the catalyzed reactions. The hydrolysis of S,S-TSO afforded by the E35Q mutant was comparable with that of the wild-type enzyme, with only a minor decrease in activity, or a change in pH dependencies of k(cat), and the rate of alkylenzyme hydrolysis, k(3). The pH dependence of E35Q-catalyzed hydrolysis of R,R-TSO, however, exhibited an inverted titration curve as compared to that of the wild-type enzyme, with a minimal catalytic rate at pH values where the wild-type enzyme exhibited maximum rates. To simulate the pH dependence of the E35Q mutant, a shift in the acidity of the alkylenzyme had to be invoked. The proposed decrease in the pK(a) of His(300) in the E35Q mutant was supported by computer simulations of the active site electrostatics. Hence, Glu(35) participates in activation of the Asp nucleophile, presumably by facilitating channeling of protons out of the active site, and during the hydrolysis half-reaction by orienting the catalytic water for optimal hydrogen bonding, to fine-tune the acid-base characteristics of the general base His(300).

National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-97211 (URN)10.1021/bi062052s (DOI)000244468000020 ()17284015 (PubMedID)
Available from: 2008-04-29 Created: 2008-04-29 Last updated: 2017-12-14Bibliographically approved
3. Continuum solvation models in the linear interaction energy method
Open this publication in new window or tab >>Continuum solvation models in the linear interaction energy method
2006 In: Journal of Physical Chemistry B, ISSN 1520-6106, Vol. 110, no 24, p. 12034-12041Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-97212 (URN)
Available from: 2008-04-29 Created: 2008-04-29Bibliographically approved
4. Improving the accuracy of the linear interaction energy method for solvation free energies
Open this publication in new window or tab >>Improving the accuracy of the linear interaction energy method for solvation free energies
2007 (English)In: Journal of Chemical Theory and Computation, ISSN 1549-9618, E-ISSN 1549-9626, Vol. 3, no 6, p. 2162-2175Article in journal (Refereed) Published
Abstract [en]

A linear response method for estimating the free energy of solvation is presented and validated using explicit solvent molecular dynamics, thermodynamic perturbation calculations, and experimental data. The electrostatic contribution to the solvation free energy is calculated using a linear response estimate, which is obtained by comparison to the free energy calculated using thermodynamic perturbation. Systematic deviations from the value of 1/2 in the potential energy scaling factor are observed for some types of compounds, and these are taken into account by introducing specific coefficients for different chemical groups. The derived model reduces the rms error of the linear response estimate significantly from 1.6 to 0.3 kcal/mol on a training set of 221 molecules used to parametrize the model and from 3.7 to 1.3 kcal/mol on a test set of 355 molecules that were not used in the derivation of the model. The total solvation free energy is estimated by combining the derived model with an empirical size dependent term for predicting the nonpolar contribution. Using this model, the experimental hydration free energies for 192 molecules are reproduced with an rms error of 1.1 kcal/mol. The use of LIE in simplified binding free energy calculations to predict protein−ligand binding free energies is also discussed.

National Category
Biological Sciences
Identifiers
urn:nbn:se:uu:diva-97213 (URN)10.1021/ct700106b (DOI)000251024200024 ()
Available from: 2008-04-29 Created: 2008-04-29 Last updated: 2017-12-14Bibliographically approved
5. Combining docking, molecular dynamics and the linear interaction energy method to predict binding modes and affinities for non-nucleoside inhibitors to HIV-1 reverse transcriptase
Open this publication in new window or tab >>Combining docking, molecular dynamics and the linear interaction energy method to predict binding modes and affinities for non-nucleoside inhibitors to HIV-1 reverse transcriptase
2008 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 51, no 9, p. 2648-56Article in journal (Refereed) Published
Abstract [en]

Docking, scoring, molecular dynamics (MD), and the linear interaction energy (LIE) method are used here to predict binding modes and affinities for a set of 43 non-nucleoside inhibitors to HIV-1 reverse transcriptase. Starting from a crystallographic structure, the binding modes of 43 inhibitors are predicted using automated docking. The Goldscore scoring function and the LIE method are then used to determine the relative binding free energies for the inhibitors. The Goldscore scoring function does not reproduce the relative binding affinities for the inhibitors, while the standard parametrization of the LIE method reproduces the experimental binding free energies for 39 inhibitors with an R (2) = 0.70 and an unsigned average error of 0.8 kcal/mol. The present calculations provide a validation of the combination of docking, MD, and LIE as a powerful tool in structure-based drug design, and the methodology is easily scalable for attaining a higher throughput of compounds.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-97214 (URN)10.1021/jm7012198 (DOI)000255500000010 ()18410085 (PubMedID)
Available from: 2008-04-29 Created: 2008-04-29 Last updated: 2017-12-14Bibliographically approved
6. Absolute and relative entropies from computer simulation with applications to ligand binding
Open this publication in new window or tab >>Absolute and relative entropies from computer simulation with applications to ligand binding
2005 In: Journal of Physical Chemistry B, ISSN 1520-6106, Vol. 109, no 13, p. 6448-6456Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-97215 (URN)
Available from: 2008-04-29 Created: 2008-04-29Bibliographically approved
7. Calculations of solute and solvent entropies from molecular dynamics simulations
Open this publication in new window or tab >>Calculations of solute and solvent entropies from molecular dynamics simulations
2006 (English)In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 8, no 46, p. 5385-5395Article in journal (Refereed) Published
Abstract [en]

The translational, rotational and conformational ( vibrational) entropy contributions to ligand-receptor binding free energies are analyzed within the standard formulation of statistical thermodynamics. It is shown that the partitioning of the binding entropy into different components is to some extent arbitrary, but an appropriate method to calculate both translational and rotational entropy contributions to noncovalent association is by estimating the configurational volumes of the ligand in the bound and free states. Different approaches to calculating solute entropies using free energy perturbation calculations, configurational volumes based on root-mean-square fluctuations and covariance matrix based quasiharmonic analysis are illustrated for some simple molecular systems. Numerical examples for the different contributions demonstrate that theoretically derived results are well reproduced by the approximations. Calculation of solvent entropies, either using total potential energy averages or van't Ho. plots, are carried out for the case of ion solvation in water. Although convergence problems will persist for large and complex simulation systems, good agreement with experiment is obtained here for relative and absolute ion hydration entropies. We also outline how solvent and solute entropic contributions are taken into account in empirical binding free energy calculations using the linear interaction energy method. In particular it is shown that empirical scaling of the nonpolar intermolecular ligand interaction energy effectively takes into account size dependent contributions to the binding free energy.

National Category
Biological Sciences
Identifiers
urn:nbn:se:uu:diva-97216 (URN)10.1039/b608486a (DOI)000242220400001 ()17119645 (PubMedID)
Available from: 2008-04-29 Created: 2008-04-29 Last updated: 2017-12-14Bibliographically approved
8. Absolute hydration entropies of alkali metal ions from molecular dynamics simulations
Open this publication in new window or tab >>Absolute hydration entropies of alkali metal ions from molecular dynamics simulations
2009 (English)In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 113, no 30, p. 10255-10260Article in journal (Refereed) Published
Abstract [en]

Molecular dynamics simulations in combination with the free energy   perturbation technique are used in this work to calculate absolute ion   hydration entropies. The hydration entropies for five alkali metal ions   are estimated from van't Hoff plots using hydration free energies   calculated at eight different temperatures. Considering that the   ion-water potentials were parametrized only on absolute hydration free   energies and ionic radii, the absolute hydration entropies agree very   well with experimental data. Simulation lengths of about 3 ns at each   temperature were required to achieve an uncertainty below 1 kcal/mol   for the entropic contribution to the hydration free energy (-T Delta   S-hyd). The uncertainties for the calculated entropies are typically   four times larger than for the free energies. The possibility to use   approximate approaches to calculate hydration entropies is also   investigated. The entropy of creating the uncharged van der Waals spheres in water correlates well with the solvent accessible surface area of the ions. The Born continuum model and the linear response   approximation cannot be used to predict the entropy of charging the van   der Waals spheres in water without introducing temperature dependent empirical parameters.

National Category
Biological Sciences
Identifiers
urn:nbn:se:uu:diva-97217 (URN)10.1021/jp900818z (DOI)000268231000030 ()
Available from: 2008-04-29 Created: 2008-04-29 Last updated: 2017-12-14Bibliographically approved

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