Assessing polyglutamine conformation in the nucleating event by molecular dynamics simulations
- Polyglutamine (polyQ) diseases comprise a group of dominantly inherited pathology caused by an expansion of an unstable polyQ stretch which is presumed to form beta-sheets. Similar to other amyloid pathologies, polyQ amyloidogenesis occurs via a nucleated polymerization mechanism, and proceeds through energetically unfavorable nucleus whose existence and structure are difficult to detect. Here, we use atomistic molecular dynamics simulations in explicit solvent to assess the conformation of the polyQ stretch in the nucleus that initiates polyQ fibrillization. Comparison of the kinetic stability of various structures of polyQ peptide with a Q-length in the pathological range (Q(40)) revealed that steric zipper or nanotube-like structures (beta-nanotube or beta-pseudohelix) are not kinetically stable enough to serve as a template to initiate polyQ fibrillization as opposed to beta-hairpin-based (beta-sheet and beta-sheetstack) or alpha-helical conformations. The selection of different structures of the polyQ stretch in thePolyglutamine (polyQ) diseases comprise a group of dominantly inherited pathology caused by an expansion of an unstable polyQ stretch which is presumed to form beta-sheets. Similar to other amyloid pathologies, polyQ amyloidogenesis occurs via a nucleated polymerization mechanism, and proceeds through energetically unfavorable nucleus whose existence and structure are difficult to detect. Here, we use atomistic molecular dynamics simulations in explicit solvent to assess the conformation of the polyQ stretch in the nucleus that initiates polyQ fibrillization. Comparison of the kinetic stability of various structures of polyQ peptide with a Q-length in the pathological range (Q(40)) revealed that steric zipper or nanotube-like structures (beta-nanotube or beta-pseudohelix) are not kinetically stable enough to serve as a template to initiate polyQ fibrillization as opposed to beta-hairpin-based (beta-sheet and beta-sheetstack) or alpha-helical conformations. The selection of different structures of the polyQ stretch in the aggregation-initiating event may provide an alternative explanation for polyQ aggregate polymorphism.…
| Author details: | Markus S. Miettinen, Volker Knecht, Luca Monticelli, Zoya Ignatova |
|---|---|
| DOI: | https://doi.org/10.1021/jp305065c |
| ISSN: | 1520-6106 |
| Title of parent work (English): | The journal of physical chemistry : B, Condensed matter, materials, surfaces, interfaces & biophysical chemistry |
| Publisher: | American Chemical Society |
| Place of publishing: | Washington |
| Publication type: | Article |
| Language: | English |
| Year of first publication: | 2012 |
| Publication year: | 2012 |
| Release date: | 2017/03/26 |
| Volume: | 116 |
| Issue: | 34 |
| Number of pages: | 7 |
| First page: | 10259 |
| Last Page: | 10265 |
| Funding institution: | Finnish Foundation for Technology Promotion (TES); HPC-Europa2 visitor project [228398]; European Commission; European Molecular Biology Organization [EMBO ALTF 1251-2010]; Deutsche Forschungsgemeinschaft [IG 73/8-1] |
| Organizational units: | Mathematisch-Naturwissenschaftliche Fakultät / Institut für Biochemie und Biologie |
| Peer review: | Referiert |
