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An evaluation of non-periodic boundary condition models in molecular dynamics simulations using prion octapeptides as probes
KTH, School of Chemical Science and Engineering (CHE), Chemistry, Inorganic Chemistry.
Physical Chemistry Department, University of Seville.
KTH, School of Chemical Science and Engineering (CHE), Chemistry, Inorganic Chemistry.
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.

Place, publisher, year, edition, pages
2006. Vol. 760, no 1-3, 91-98 p.
Keyword [en]
Molecular dynamics; Non-periodic boundary conditions; Prion protein; Solvation model
National Category
Inorganic Chemistry
Identifiers
URN: urn:nbn:se:kth:diva-7295DOI: 10.1016/j.theochem.2005.11.027ISI: 000236566300011Scopus ID: 2-s2.0-33644817645OAI: oai:DiVA.org:kth-7295DiVA: diva2:12259
Note
QC 20100816Available from: 2007-06-04 Created: 2007-06-04 Last updated: 2010-08-16Bibliographically approved
In thesis
1. A Theoretical Investigation of the Octapeptide Region in the Human Prion Protein
Open this publication in new window or tab >>A Theoretical Investigation of the Octapeptide Region in the Human Prion Protein
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
prion protein; copper; octapeptide; structure; force field parameters; coordination; non-periodic boundary conditions
National Category
Inorganic Chemistry
Identifiers
urn:nbn:se:kth:diva-4423 (URN)987-91-7178-719-4 (ISBN)
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
2. Structure and Dynamics of the Copper-binding Octapeptide Region in the Human Prion Protein
Open this publication in new window or tab >>Structure and Dynamics of the Copper-binding Octapeptide Region in the Human Prion Protein
2005 (English)Licentiate 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.

Place, publisher, year, edition, pages
Stockholm: KTH, 2005. 40 p.
Series
Trita-OOK, ISSN 0348-825X ; 1080
Keyword
Inorganic chemistry, prion protein, copper, molecular dynamics simulation, solvation model, metal ions, coordination, Oorganisk kemi
National Category
Inorganic Chemistry
Identifiers
urn:nbn:se:kth:diva-250 (URN)
Presentation
2005-05-27, E3, Huvudbyggnaden, Osquarsbacke 14, Stockholm, 10:00
Supervisors
Note
QC 20101220Available from: 2005-05-31 Created: 2005-05-31 Last updated: 2010-12-20Bibliographically approved

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