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Molecular dynamics study of zinc binding to cysteines in a peptide mimic of the alcohol dehydrogenase structural zinc site
KTH, School of Engineering Sciences (SCI), Theoretical Physics.
KTH, School of Chemical Science and Engineering (CHE), Chemistry, Physical Chemistry.ORCID iD: 0000-0003-2673-075X
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2009 (English)In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 11, no 6, 975-983 p.Article in journal (Refereed) Published
Abstract [en]

The binding of zinc (Zn) ions to proteins is important for many cellular events. The theoretical and computational description of this binding (as well as that of other transition metals) is a challenging task. In this paper the binding of the Zn ion to four cysteine residues in the structural site of horse liver alcohol dehydrogenase (HLADH) is studied using a synthetic peptide mimic of this site. The study includes experimental measurements of binding constants, classical free energy calculations from molecular dynamics (MD) simulations and quantum mechanical (QM) electron structure calculations. The classical MD results account for interactions at the molecular level and reproduce the absolute binding energy and the hydration free energy of the Zn ion with an accuracy of about 10%. This is insufficient to obtain correct free energy differences. QM correction terms were calculated from density functional theory (DFT) on small clusters of atoms to include electronic polarisation of the closest waters and covalent contributions to the Zn-S coordination bond. This results in reasonably good agreement with the experimentally measured binding constants and Zn ion hydration free energies in agreement with published experimental values. The study also includes the replacement of one cysteine residue to an alanine. Simulations as well as experiments showed only a small effect of this upon the binding free energy. A detailed analysis indicate that the sulfur is replaced by three water molecules, thereby changing the coordination number of Zn from four (as in the original peptide) to six (as in water).

Place, publisher, year, edition, pages
2009. Vol. 11, no 6, 975-983 p.
Keyword [en]
Alcohol Dehydrogenase, Amino Acid Sequence, Animals, Binding Sites, Biomimetic Materials, Cysteine, Horses, Liver, Models, Molecular, Molecular Conformation, Peptides, Quantum Theory, Thermodynamics, Zinc
National Category
Condensed Matter Physics
URN: urn:nbn:se:kth:diva-10292DOI: 10.1039/b815482aISI: 000262850600011PubMedID: 19177216ScopusID: 2-s2.0-84962439482OAI: diva2:214411
QC 20100923Available from: 2009-05-05 Created: 2009-05-05 Last updated: 2010-09-23Bibliographically approved
In thesis
1. Interactions and dynamics in biophysical model systems
Open this publication in new window or tab >>Interactions and dynamics in biophysical model systems
2009 (English)Licentiate thesis, comprehensive summary (Other academic)
Abstract [en]

Computer simulations of simplified model systems provide understanding of how complex biological systems behave. The simulations give detailed information about the systems, with atomistic resolution, that can be used in combination with experimental knowledge to shed light on underlying physical principles. The thesis presents background information about the studies of two important model systems in biological physics.

First, metal ion-binding to proteins is investigated in a computational study on a zinc-binding synthetic peptide, to elucidate the binding details. The major scientific contributions from the study are the identification and mapping of the detailed contributions to the binding. A novel correction scheme is worked out, where classic free energy calculations are combined with density functional theory to adjust for quantum mechanical effects.  The sensitivity of the zinc-binding to a specific amino acid segment can be explained in terms of the zinc coordination.

Second, equilibrium density fluctuations in biological membranes are studied using computer simulations of the lipid bilayer. The fluctuations are linked to several processes; pore formation, membrane permeability and transport of small molecules across themembrane. Because the lipid bilayer behaves similar to a 2D fluid the density fluctuations can be described in the framework of generalized hydrodynamics. The major scientific contributions from the study are the direct calculation of the density-density autocorrelation function from raw data and the observation that the diffusive contribution to the power spectrum (the Rayleigh line) is not single-exponential. In addition, the accuracy of the approximate hydrodynamic solutions is questionable for the propagation of sound waves in the membrane.

Place, publisher, year, edition, pages
Stockholm: KTH, 2009. ix, 51 p.
Trita-FYS, ISSN 0280-316X ; 2009:18
National Category
Condensed Matter Physics
urn:nbn:se:kth:diva-10300 (URN)978-91-7415-355-2 (ISBN)
2009-05-29, FA32, Albanova Universitetscenter, Stockholm, 10:00 (English)
Available from: 2009-05-18 Created: 2009-05-05 Last updated: 2010-11-03Bibliographically approved

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