Journal article
Folding events in the 21-30 region of amyloid beta-protein (Abeta) studied in silico
Proceedings of the National Academy of Sciences - PNAS, v 102(17), pp 6015-6020
26 Apr 2005
PMID: 15837927
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Oligomeric assemblies of the amyloid beta-protein (Abeta) have been implicated in the pathogenesis of Alzheimer's disease as a primary source of neurotoxicity. Recent in vitro studies have suggested that a 10-residue segment, Ala-21-Ala-30, forms a turn-like structure that nucleates the folding of the full-length Abeta. To gain a mechanistic insight, we simulated Abeta(21-30) folding by using a discrete molecular dynamics algorithm and a united-atom model incorporating implicit solvent and a variable electrostatic interaction strength (EIS). We found that Abeta(21-30) folds into a loop-like conformation driven by an effective hydrophobic attraction between Val-24 and the butyl portion of the Lys-28 side chain. At medium EIS [1.5 kcal/mol (1 cal = 4.18 J)], unfolded conformations almost disappear, in agreement with experimental observations. Under optimal conditions for folding, Glu-22 and Asp-23 form transient electrostatic interactions (EI) with Lys-28 that stabilize the loop conformations. Glu-22-Lys-28 is the most favored interaction. High EIS, as it occurs in the interior of proteins and aggregates, destabilizes the packing of Val-24 and Lys-28. Analysis of the unpacked structures reveals strong EI with predominance of the Asp-23-Lys-28 interaction, in agreement with studies of molecular modeling of full-length Abeta fibrils. The binary nature of the EI involving Lys-28 provides a mechanistic explanation for the linkage of amino acid substitutions at Glu-22 with Alzheimer's disease and cerebral amyloid angiopathy. Substitutions may alter the frequency of Glu-22 or Asp-23 involvement in contact formation and affect the stability of the folding nucleus formed in the Abeta(21-30) region.
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Details
- Title
- Folding events in the 21-30 region of amyloid beta-protein (Abeta) studied in silico
- Creators
- Jose M Borreguero - Center for Polymer Studies and Department of Physics, Boston University, Boston, MA 02215, USA. jmborr@bu.eduBrigita UrbancNoel D LazoSergey V BuldyrevDavid B TeplowH Eugene Stanley
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, v 102(17), pp 6015-6020
- Publisher
- PNAS; United States
- Grant note
- R01 AG018921 / NIA NIH HHS NS44147 / NINDS NIH HHS NS38328 / NINDS NIH HHS AG18921 / NIA NIH HHS R01 NS038328 / NINDS NIH HHS R01 NS044147 / NINDS NIH HHS R21-AG-D23661 / NIA NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Physics
- Web of Science ID
- WOS:000228738800024
- Scopus ID
- 2-s2.0-17844410343
- Other Identifier
- 991014878436104721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Biochemistry & Molecular Biology