uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Characterization of Mn(II) ion binding to the amyloid-beta peptide in Alzheimer's disease
Stockholm Univ, Dept Biochem & Biophys, Svante Arrhenius Vag 16C, S-10691 Stockholm, Sweden..
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structure and Molecular Biology.
Stockholm Univ, Dept Biochem & Biophys, Svante Arrhenius Vag 16C, S-10691 Stockholm, Sweden.;Karolinska Inst, Div Neurogeriatr, Dept Neurobiol Care Sci & Soc NVS, H1,Novum Pl 5, S-14157 Stockholm, Sweden..
Stockholm Univ, Dept Biochem & Biophys, Svante Arrhenius Vag 16C, S-10691 Stockholm, Sweden.;NICPB, Akad Tee 23, EE-12618 Tallinn, Estonia..
Show others and affiliations
2016 (English)In: Journal of Trace Elements in Medicine and Biology, ISSN 0946-672X, E-ISSN 1878-3252, Vol. 38, p. 183-193Article in journal (Refereed) Published
Abstract [en]

Growing evidence links neurodegenerative diseases to metal exposure. Aberrant metal ion concentrations have been noted in Alzheimer's disease (AD) brains, yet the role of metals in AD pathogenesis remains unresolved. A major factor in AD pathogenesis is considered to be aggregation of and amyloid formation by amyloid-beta (A beta) peptides. Previous studies have shown that A beta displays specific binding to Cu(II) and Zn(II) ions, and such binding has been shown to modulate A beta aggregation. Here, we use nuclear magnetic resonance (NMR) spectroscopy to show that Mn(II) ions also bind to the N-terminal part of the A beta(1-40) peptide, with a weak binding affinity in the milli- to micromolar range. Circular dichroism (CD) spectroscopy, solid state atomic force microscopy (AFM), fluorescence spectroscopy, and molecular modeling suggest that the weak binding of Mn(II) to A beta may not have a large effect on the peptide's aggregation into amyloid fibrils. However, identification of an additional metal ion displaying A beta binding reveals more complex AD metal chemistry than has been previously considered in the literature.

Place, publisher, year, edition, pages
2016. Vol. 38, p. 183-193
Keywords [en]
Manganese, Neurodegeneration, Metal-protein binding, Spectroscopy, Molecular dynamics
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-308063DOI: 10.1016/j.jtemb.2016.03.009ISI: 000385473600023PubMedID: 27085215OAI: oai:DiVA.org:uu-308063DiVA, id: diva2:1050888
Available from: 2016-11-30 Created: 2016-11-23 Last updated: 2019-12-04Bibliographically approved
In thesis
1. Computational Modeling of the Structure, Function and Dynamics of Biomolecular Systems
Open this publication in new window or tab >>Computational Modeling of the Structure, Function and Dynamics of Biomolecular Systems
2020 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Proteins are a structurally diverse and functionally versatile class of biomolecules. They perform a variety of life-sustaining biological processes with utmost efficiency. A profound understanding of protein function requires knowledge of its structure. Experimentally determined protein structures can serve as a starting point for computer simulations in order to study their dynamic behavior at a molecular level. In this thesis, computational methods have been used to understand structure-function relationships in two classes of proteins - intrinsically disordered proteins (IDP) and enzymes.

Misfolding and subsequent aggregation of the amyloid beta (Aβ) peptide, an IDP, is associated with the progression of Alzheimer’s disease. Besides enriching our understanding of structural dynamics, computational studies on a medically relevant IDP such as Aβ can potentially guide therapeutic development. In the present work, binding interactions of the monomeric form of this peptide with biologically relevant molecular species such as divalent metal ions (Zn2+, Cu2+, Mn2+) and amphiphilic surfactants were characterized using long timescale molecular dynamics (MD) simulations. Among the metal ions, while Zn2+ and Cu2+ maintained coordination to a well-defined binding site in Aβ, Mn2+-binding was observed to be comparatively weak and transient. Surfactants with charged headgroups displayed strong binding interaction with Aβ. Complemented by biophysical experiments, these studies provided a multifaceted perspective of Aβ interactions with the partner molecules.

Triosephosphate isomerase (TIM), a highly evolved and catalytically proficient enzyme, was studied using empirical valence bond (EVB) calculations to obtain deeper insights into the catalytic reaction mechanism. Multiple structural features of TIM such as the flexible loop and preorganized active site residues were investigated for their role in enzyme catalysis. The effect of substrate binding was also studied using truncated substrates. Finally, using enhanced sampling methods, dynamic behavior of the catalytically important loop 6 was characterized. The importance of structural stability and flexibility on protein function was illustrated by the work presented in this thesis, thus furthering our scientific understanding of proteins at a molecular level.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2020. p. 72
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1885
Keywords
Molecular Dynamics, Empirical Valence Bond, Enzyme Catalysis, Amyloid Beta, Aβ, Triosephosphate Isomerase, TIM, Computational Biochemistry, Computational Enzymology
National Category
Biochemistry and Molecular Biology Theoretical Chemistry
Research subject
Biochemistry
Identifiers
urn:nbn:se:uu:diva-398169 (URN)978-91-513-0828-9 (ISBN)
Public defence
2020-02-05, B21, BMC, Husargatan 3, Uppsala, 13:15 (English)
Opponent
Supervisors
Available from: 2020-01-14 Created: 2019-12-04 Last updated: 2020-01-14

Open Access in DiVA

fulltext(1940 kB)67 downloads
File information
File name FULLTEXT01.pdfFile size 1940 kBChecksum SHA-512
aa18582180ab4a6ae68f61ba92f62a92b65f7cf3f2dc53b119617c43eafa3b728e2da3dcf400b10c3db967988720c07a00ea3c0f951e54cb93d08c1880ee8ae6
Type fulltextMimetype application/pdf

Other links

Publisher's full textPubMed

Authority records BETA

Kulkarni, Yashraj S.Kamerlin, Shina C. L.

Search in DiVA

By author/editor
Kulkarni, Yashraj S.Kamerlin, Shina C. L.
By organisation
Structure and Molecular Biology
In the same journal
Journal of Trace Elements in Medicine and Biology
Cell and Molecular Biology

Search outside of DiVA

GoogleGoogle Scholar
Total: 67 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 418 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf