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A Theoretical Investigation of the Octapeptide Region in the Human Prion Protein
KTH, School of Chemical Science and Engineering (CHE), Chemistry.
2007 (English)Doctoral thesis, comprehensive summary (Other scientific)
Abstract [sv]

Den kopparbindande egenskapen hos prionproteiner är sannolikt kopplad till proteinets funtion. Det mänskliga prionproteinet innehåller ett kopparbindande oktapeptidområde, där PHGGGWGQ-sekvensen upprepas fyra gånger i följd. Syftet med detta arbete är att undersöka strukturen och dynamiken i oktapeptidområdet genom att använda teoretiska metoder. Med kvantkemisk strukturoptimering genomfördes en detaljerad jämförelse av växelverkan mellan flera katjoner och det kopparbindande området. Enligt dessa beräkningar är rodium(III) en möjlig ersättare för koppar(II) i NMR-specktroskopiska koordinationsstudier. Alternativa solvatiseringsmodeller i molekyldynamiksimuleringar har också jämförts. Periodiska randvillkor är mest lämpade för användning i de system som undersöks i detta arbete. Molekyldynamiksimuleringar användes för att jämföra oktapeptidområdets struktur och dynamik med och utan kopparjoner. Växelverkan mellan aminosyrornas ringar påverkar starkt strukturen i detta område i frånvaro av kopparjoner. Fyra olika icke-bindande och bindande modeller har studerats, vilka skiljer i sin beskrivning av växelverkan mellan koppar och proteinet. Teoretiska EXAFS spektra beräknades från dem simulerade strukturerna. Spektra som genererats för den bindande modellen är nästan identiska med experimentiella resultat, vilket stöder användandet av den bindande modellen. Detta arbete visar att kopparjoner interagerar med histidin imidazolringens Nδ, deprotonerade amidkväven hos de därpå följande glycinerna samt karbonylsyret hos den andra glycinen. Simuleringarna kunde visa att kopparjonen inte stabilt binder några axiella vattenmolekyler i lösning, till skillnad från en kristallstruktur av koordinationsstrukturen. Indolringen hos tryptofan interagerar direkt med kopparjonen genom stabiliserande katjon-π växelverkan utan direkt medverkan av någon vattenmolekyl. Växelverkan mellan indolringen och kopparjonen var väldefinierad och observerades kunna ske på båda sidor av koordinationsplanet. Molekyldynamiksimuleringarna med kopparjoner och oktapeptidområdet visade hur närvaron av kopparjoner ledde till ett mer strukturerat oktapeptidområde.

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.

Place, publisher, year, edition, pages
Stockholm: KTH , 2007. , x, 73 p.
Series
Trita-CHE-Report, ISSN 1654-1081 ; 2007:40
Keyword [en]
prion protein; copper; octapeptide; structure; force field parameters; coordination; non-periodic boundary conditions
National Category
Inorganic Chemistry
Identifiers
URN: urn:nbn:se:kth:diva-4423ISBN: 987-91-7178-719-4 OAI: oai:DiVA.org:kth-4423DiVA: diva2:12264
Public defence
2007-06-15, Sydvästra galleriet, KTHB, Osquars backe 31, Stockholm, 10:00
Opponent
Supervisors
Note
QC 20100816Available from: 2007-06-04 Created: 2007-06-04 Last updated: 2010-08-16Bibliographically approved
List of papers
1. An evaluation of non-periodic boundary condition models in molecular dynamics simulations using prion octapeptides as probes
Open this publication in new window or tab >>An evaluation of non-periodic boundary condition models in molecular dynamics simulations using prion octapeptides as probes
2006 (English)In: Journal of Molecular Structure: THEOCHEM, ISSN 0166-1280, Vol. 760, no 1-3, 91-98 p.Article in journal (Refereed) Published
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.

Keyword
Molecular dynamics; Non-periodic boundary conditions; Prion protein; Solvation model
National Category
Inorganic Chemistry
Identifiers
urn:nbn:se:kth:diva-7295 (URN)10.1016/j.theochem.2005.11.027 (DOI)000236566300011 ()2-s2.0-33644817645 (Scopus ID)
Note
QC 20100816Available from: 2007-06-04 Created: 2007-06-04 Last updated: 2017-12-14Bibliographically approved
2. Computational Comparison of Cation Coordination to Human Prion Peptide Models
Open this publication in new window or tab >>Computational Comparison of Cation Coordination to Human Prion Peptide Models
2006 (English)In: Inorganic Chemistry, ISSN 0020-1669, E-ISSN 1520-510X, Vol. 45, no 21, 8509-8516 p.Article in journal (Refereed) Published
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.

Keyword
copper; divalent cation; iron; nickel; peptide fragment; platinum; rhodium; zinc; article; chemical structure; chemistry; human; metabolism; nuclear magnetic resonance spectroscopy; prion; protein conformation; Cations, Divalent; Copper; Humans; Iron; Magnetic Resonance Spectroscopy; Models, Molecular; Nickel; Peptide Fragments; Platinum; Prions; Protein Conformation; Rhodium; Zinc
National Category
Inorganic Chemistry
Identifiers
urn:nbn:se:kth:diva-7296 (URN)10.1021/ic052079k (DOI)000241106700013 ()2-s2.0-33750345360 (Scopus ID)
Note
QC 20100816Available from: 2007-06-04 Created: 2007-06-04 Last updated: 2017-12-14Bibliographically approved
3. Molecular dynamics Simulations of Cu(II) and the PHGGGWGQ octapeptide
Open this publication in new window or tab >>Molecular dynamics Simulations of Cu(II) and the PHGGGWGQ octapeptide
2007 (English)In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 111, no 35, 10529-10537 p.Article in journal (Refereed) Published
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.

Keyword
deriving atomic charges, avian prion protein, copper-binding, octarepeat domain, force-field, coordination, hydration, regions, models, sites
National Category
Inorganic Chemistry
Identifiers
urn:nbn:se:kth:diva-16927 (URN)10.1021/jp072672i (DOI)000249169800025 ()2-s2.0-34548858451 (Scopus ID)
Note
QC 20100816Available from: 2010-08-05 Created: 2010-08-05 Last updated: 2017-12-12Bibliographically approved
4. Structural effects of Cu(II)-coordination in the octapeptide region of the human prion protein
Open this publication in new window or tab >>Structural effects of Cu(II)-coordination in the octapeptide region of the human prion protein
2008 (English)In: Physical Chemistry, Chemical Physics - PCCP, ISSN 1463-9076, E-ISSN 1463-9084, Vol. 10, no 18, 2488-2495 p.Article in journal (Refereed) Published
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.

Keyword
copper; oligopeptide; tryptophan; article; chemical structure; chemistry; drug effect; human; prion; protein binding; rotation; thermodynamics; Copper; Humans; Models, Molecular; Oligopeptides; Prions; Protein Binding; Rotation; Thermodynamics; Tryptophan
National Category
Inorganic Chemistry
Identifiers
urn:nbn:se:kth:diva-17491 (URN)10.1039/b717988j (DOI)000255449200006 ()2-s2.0-43049145009 (Scopus ID)
Note
QC 20100816Available from: 2010-08-05 Created: 2010-08-05 Last updated: 2017-12-12Bibliographically approved
5. Theoretical EXAFS Studies of the Cu(II)-Octapeptide Complex
Open this publication in new window or tab >>Theoretical EXAFS Studies of the Cu(II)-Octapeptide Complex
(English)Manuscript (Other academic)
National Category
Inorganic Chemistry
Identifiers
urn:nbn:se:kth:diva-7299 (URN)
Note
QC 20100816Available from: 2007-06-04 Created: 2007-06-04 Last updated: 2010-08-16Bibliographically approved

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