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Molecular dynamics simulations of Zn2+ coordination in protein binding sites
KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical Biological Physics.
KTH, School of Engineering Sciences (SCI), Theoretical Physics, Theoretical Biological Physics.ORCID iD: 0000-0002-7448-4664
2010 (English)In: Journal of Chemical Physics, ISSN 0021-9606, E-ISSN 1089-7690, Vol. 132, no 20, 205101- p.Article in journal (Refereed) Published
Abstract [en]

A systematic molecular dynamics (MD) study of zinc binding to a peptide that mimics the structural binding site of horse liver alcohol dehydrogenase (HLADH) has been conducted. The four zinc binding cysteines were successively mutated into alanines to study the stability, zinc coordination, and free energy of binding. The zinc ion is coordinated to four sulfurs in the native peptide as in x-ray structures of HLADH. When the cysteines are replaced by alanines, the zinc coordinating sulfurs are replaced by waters and/or polypeptide backbone carbonyl oxygens. With two or fewer cysteines, the coordination number increases from four to six, while the coordination number varies between four and six with three cysteines depending on which of the cysteines that is replaced by an alanine. The binding free energies of zinc to the proteins were calculated from MD free energy integration runs to which corrections from quantum mechanical cluster calculations were added. There is a reasonable correlation with experimental binding free energies [T. Bergman , Cell. Mol. Life Sci. 65, 4019 (2008)]. For the chains with the lowest structural fluctuations and highest free energies lower coordination numbers for zinc are obtained. Finally, x-ray absorption fine structure spectra were calculated from the MD structures.

Place, publisher, year, edition, pages
2010. Vol. 132, no 20, 205101- p.
Keyword [en]
binding energy, coupled cluster calculations, EXAFS, molecular dynamics method, proteins, zinc
National Category
Physical Sciences
Identifiers
URN: urn:nbn:se:kth:diva-27544DOI: 10.1063/1.3428381ISI: 000278183100033Scopus ID: 2-s2.0-77953075511OAI: oai:DiVA.org:kth-27544DiVA: diva2:379089
Funder
Swedish Research Council
Note
QC 20101217Available from: 2010-12-17 Created: 2010-12-13 Last updated: 2017-12-11Bibliographically approved
In thesis
1. Classical and Quantum Descriptions of Proteins, Lipids and Membranes
Open this publication in new window or tab >>Classical and Quantum Descriptions of Proteins, Lipids and Membranes
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In this thesis the properties of proteins and membranes are studied by molecular dynamics simulations. The subject is decomposed into parts addressing free energy calculations in proteins, mechanical inclusion models for lipid bilayers, phase transitions and structural correlations in lipid bilayers and atomistic lipid bilayer models. The work is based on results from large scale computer simulations, quantum mechanical and continuum models. Efficient statistical sampling and the coarseness of the models needed to describe the ordered and disordered states are of central concern.

Classical free energy calculations of zinc binding, in metalloproteins, require a quantum mechanical correction in order to obtain realistic binding energies. Classical electrostatic polarisation will influence the binding energy in a large region surrounding the ion and produce reasonable equilibrium structures in the bound state, when compared to experimental evidence.

The free energy for inserting a protein into a membrane is calculated with continuum theory. The free energy is assumed quadratic in the mismatch and depend on two elastic constants of the membrane. Under these circumstances, the free energy can then be written as a line tension multiplied by the circumference of the membrane inclusion. The inclusion model and coarse grained particle simulations of the membranes show that the thickness profile around the protein will be an exponentially damped oscillation.

Coarse-grained particle simulations of model membranes containing mixtures of phospholipid and cholesterol molecules at different conditions were performed. The gel-to-liquid crystalline phase transition is successively weakened with increasing amounts of cholesterol without disappearing even at a concentration of cholesterol as high as 60%.

A united atom parameterization of diacyl lipids was constructed. The aim was to construct a new force field that retains and improves the good agreement for the fluid phase and at the same time produces a gel phase at low temperatures, with properties coherent with experimental findings. The global bilayer tilt obtains an azimuthal value of 31and is aligned between lattice vectors in the bilayer plane. It is also shown that the model yield a correct heat of melting as well as heat capacities in the fluid and gel phase of DPPC.

 

Place, publisher, year, edition, pages
Stockholm, Sweden: KTH Royal Institute of Technology, 2014. xiv, 73 p.
Series
TRITA-FYS, ISSN 0280-316X ; 2014:55
Keyword
Quantum corrections, Coordination structure, Polarisation, Phase transitions, Kelvin differential equation, Line tension, Elastic membrane models, Molecular particle models, Zinc binding, Cholesterol and Phospholipids
National Category
Physical Sciences
Research subject
Biological Physics
Identifiers
urn:nbn:se:kth:diva-151396 (URN)978-91-7595-253-6 (ISBN)
Public defence
2014-10-03, Sal FA32, AlbaNova Universitetscentrum, Roslagstullsbacken 21, Stockholm, 10:00 (English)
Opponent
Supervisors
Funder
Swedish Research Council
Note

QC 20140919

Available from: 2014-09-19 Created: 2014-09-19 Last updated: 2014-10-07Bibliographically approved

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Edholm, Olle

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