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  • 1.
    Riihimäki, Eva-Stina
    KTH, School of Chemical Science and Engineering (CHE), Chemistry.
    A Theoretical Investigation of the Octapeptide Region in the Human Prion Protein2007Doctoral thesis, comprehensive summary (Other scientific)
    Abstract [en]

    The copper-binding ability of the prion protein is thought to be closely related to its function. The human prion protein contains a copper-binding octapeptide region, where the octapeptide PHGGGWGQ is repeated four times consecutively. This work focuses on investigation of the structure and the dynamics of the octapeptide region by means of theoretical methods. Quantum chemical structural optimization allowed a detailed comparison of the interaction of several cations at the copper coordination site. These calculations identified rhodium(III) as a potent substitute for copper(II) that could be used to study the coordination site with NMR-spectroscopic methods. Solvation models that could be used in molecular dynamics simulations as an alternative to periodic boundary conditions were evaluated. Periodic boundary conditions are the best method for modeling the aqueous bulk in the kind of systems that are studied in this work. Molecular dynamics simulations were used to compare the behavior of the octapeptide region in the absence and presence of copper ions. Interaction between nonpolar rings strongly influences the structure of the region in the absence of copper ions. Four different non-bonded and bonded models for describing the interaction between copper and the protein were evaluated. Theoretical EXAFS spectra were calculated from the simulated structures. The results obtained for the bonded model are nearly identical with experimental data, which validates the use of the bonded model. This work thus shows strong evidence for copper(II) ions interacting with the octapeptide region through the histidine imidazole Nδ, the deprotonated nitrogen atoms of the following two glycine residues and the carbonyl oxygen atom of the second glycine residue. Notably, the simulations show that the axial sites of the copper ion do not stably coordinate water molecules in solution, as opposed to the crystal structure reported for the coordination site. Instead, the tryptophan indole ring interacted directly with the copper ion through stabilizing cation-π interaction without water mediation. The interaction of the indole ring with the copper ion was well-defined and was observed to occur on both sides of the coordination plane. The investigations of the interaction between copper ions and the octapeptide region with molecular dynamics simulations show how the presence of copper ions results in a more structured octapeptide region.

  • 2.
    Riihimäki, Eva-Stina
    KTH, School of Chemical Science and Engineering (CHE), Chemistry.
    Structure and Dynamics of the Copper-binding Octapeptide Region in the Human Prion Protein2005Licentiate thesis, comprehensive summary (Other scientific)
    Abstract [en]

    The copper-binding ability of the prion protein may be closely connected to its function. Identifying the exact function of the prion protein can clarify the underlying mechanism in prion diseases. In this work, the copper-binding octapeptide region in the human prion protein has been studied. The structural characteristics of the binding site are examined by quantum chemical structural optimization. The calculations aim at identifying a substitute for copper(II) to be used in NMR-spectroscopic studies of the copper-binding region. The dynamical and structural features of the peptide region are investigated in molecular dynamics simulations. Aspects of importance in the development of model systems in molecular dynamics simulation are addressed.

  • 3.
    Riihimäki, Eva-Stina
    et al.
    KTH, School of Chemical Science and Engineering (CHE), Chemistry, Inorganic Chemistry.
    Kloo, Lars
    KTH, School of Chemical Science and Engineering (CHE), Chemistry, Inorganic Chemistry.
    Computational Comparison of Cation Coordination to Human Prion Peptide Models2006In: Inorganic Chemistry, ISSN 0020-1669, E-ISSN 1520-510X, Vol. 45, no 21, p. 8509-8516Article in journal (Refereed)
    Abstract [en]

    The coordination of the cations Cu(II), Co(II), Rh(III), Ir(III), Ni(II), Pd(II), Pt(II), and Zn(II) to the copper-binding octapeptide region in the human prion protein has been compared through structural optimization. The initial coordination mode used in the calculations is a five-coordinated mode obtained from previously published crystallographic data for Cu(II). The computational results show that, among these cations, the coordinations of Co(II) and Rh(III) are the most similar to that of Cu(II). The cations Ni(II), Pd(II), and Pt(II) prefer a four-coordinate square-planar coordination by the peptide ligand. The paramagnetic Co(II) ion with its large quadrupole moment is not a good substitute for Cu(II) to be used in NMR spectroscopic studies of the coordinated peptide region. Rh(III) has more attractive NMR spectroscopic characteristics than Cu(II) and Co(II) and may represent a suitable substitute for Cu(II) in these types of studies. Some preliminary experimental studies using NMR spectroscopic methods indicate that Rh(III) coordinates the copper-binding octapeptide region of the human prion protein, although further studies are required to determine the mode of interaction in detail.

  • 4.
    Riihimäki, Eva-Stina
    et al.
    KTH, School of Chemical Science and Engineering (CHE), Chemistry.
    Kloo, Lars
    KTH, School of Chemical Science and Engineering (CHE), Chemistry.
    Sánchez Marcos, Enrique
    Martínez, José Manuel
    Theoretical EXAFS Studies of the Cu(II)-Octapeptide ComplexManuscript (Other academic)
  • 5.
    Riihimäki, Eva-Stina
    et al.
    KTH, School of Chemical Science and Engineering (CHE), Chemistry, Inorganic Chemistry.
    Manuel Martinez, Jose
    Physical Chemistry Department, University of Seville.
    Kloo, Lars A.
    KTH, School of Chemical Science and Engineering (CHE), Chemistry, Inorganic Chemistry.
    Structural effects of Cu(II)-coordination in the octapeptide region of the human prion protein2008In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 10, no 18, p. 2488-2495Article in journal (Refereed)
    Abstract [en]

    The copper-binding ability of the prion protein is thought to be central to its function. The structural effects of copper coordination in the octapeptide region of the human prion protein have been investigated by molecular dynamics simulations. Simulations were performed with the apo state, in order to investigate the behavior of the region without copper ions, as well as with the octapeptide region in the presence of copper ions. While the structure of the apo state is greatly influenced by the interaction between the rings in the histidine, tryptophan and proline residues, the region shows evidence of highly ordered coordination sites in the presence of copper ions. The position of the tryptophan indole ring is stabilized by cation-pi interactions. Two stable orientations of the indole ring with respect to the equatorial coordination plane of copper were observed, which showed that the indole ring can reside on both sides of the coordination plane. The interaction with the indole ring was found to occur without a mediating axial water molecule.

  • 6.
    Riihimäki, Eva-Stina
    et al.
    KTH, School of Chemical Science and Engineering (CHE), Chemistry, Inorganic Chemistry.
    Martinez, Jose Manuel
    Physical Chemistry Department, University of Seville.
    Kloo, Lars A.
    KTH, School of Chemical Science and Engineering (CHE), Chemistry, Inorganic Chemistry.
    Molecular dynamics Simulations of Cu(II) and the PHGGGWGQ octapeptide2007In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 111, no 35, p. 10529-10537Article in journal (Refereed)
    Abstract [en]

    The interaction between Cu2+ and the copper-binding octapeptide region in the human prion protein has been investigated by molecular dynamics simulations. In total four different nonbonded and bonded models were used in the study. Charge sets containing atomic partial charges were developed for these models. Out of the considered models, the bonded model performed physically in the most correct way. The simulations with the bonded model showed that the water molecules in the axial position are very labile. The tryptophan indole ring, can remain in a stable position on top of the equatorial coordination plane of copper without water mediation. Strong aromatic interaction was observed between the imidazole and indole rings. The nonbonded models showed a tendency for water-mediated interaction between the copper ion and different carbonyl oxygen atoms. In the case of the bonded model, a carbonyl group could also interact directly with the copper ion in one of the apical position.

  • 7.
    Riihimäki, Eva-Stina
    et al.
    KTH, School of Chemical Science and Engineering (CHE), Chemistry, Inorganic Chemistry.
    Martínez, José Manuel
    Physical Chemistry Department, University of Seville.
    Kloo, Lars
    KTH, School of Chemical Science and Engineering (CHE), Chemistry, Inorganic Chemistry.
    An evaluation of non-periodic boundary condition models in molecular dynamics simulations using prion octapeptides as probes2006In: Journal of Molecular Structure: THEOCHEM, ISSN 0166-1280, Vol. 760, no 1-3, p. 91-98Article in journal (Refereed)
    Abstract [en]

    Molecular dynamics simulations have been performed under periodic boundary conditions and using four non-periodic solvation models. The biomolecular probe in these simulations was a single repeat of the copper-binding octapeptide in the human prion protein, PHGGGWGQ. Although the alternative non-periodic solvation models enable a reduction in computational time, the dynamical disadvantages are considerable when using any of these four non-periodic models. For simulations of systems similar to the test system, periodic boundary conditions are a better alternative than any of the four local models.

  • 8.
    Riihimäki, Eva-Stina
    et al.
    KTH, School of Chemical Science and Engineering (CHE), Chemistry, Inorganic Chemistry.
    Martínez, José Manuel
    Kloo, Lars
    KTH, School of Chemical Science and Engineering (CHE), Chemistry, Inorganic Chemistry.
    Molecular Dynamics Simulations of the Copper-binding Octapeptide Region in the Human Prion ProteinArticle in journal (Refereed)
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