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Impact of sequence on the molecular assembly of short amyloid peptides

Title
Impact of sequence on the molecular assembly of short amyloid peptides
Authors
Wagoner, VA[Wagoner, Victoria A.]Cheon, M[Cheon, Mookyung]Chang, I[Chang, Iksoo]Hall, CK[Hall, Carol K.]
DGIST Authors
Cheon, M[Cheon, Mookyung]; Chang, I[Chang, Iksoo]
Issue Date
2014-07
Citation
Proteins: Structure, Function and Bioinformatics, 82(7), 1469-1483
Type
Article
Article Type
Article
Keywords
Amino Acid SequenceAmyloidAmyloid Beta-PeptidesAmyloid Beta ProteinAmyloid Beta Protein[1-40]Amyloid Beta Protein[1-42]Amyloid Beta Protein[25-35]ChemistryCoarse-Grained ModelDiscontinuous Molecular DynamicsHydrogen BondMetabolismMolecular DynamicsMolecular Dynamics SimulationPRIME20Priority JournalProtein AggregationProtein AssemblyProtein ConformationProtein ExpressionProtein StructureShort Amyloid PeptidesTemperature DependenceX Ray Diffraction
ISSN
0887-3585
Abstract
The goal of this work is to understand how the sequence of a protein affects the likelihood that it will form an amyloid fibril and the kinetics along the fibrillization pathway. The focus is on very short fragments of amyloid proteins since these play a role in the fibrillization of the parent protein and can form fibrils themselves. Discontinuous molecular dynamics simulations using the PRIME20 force field were performed of the aggregation of 48-peptide systems containing SNQNNF (PrP (170-175)), SSTSAA (RNaseA(15-20)), MVGGVV (Aβ(35-40)), GGVVIA (Aβ(37-42)), and MVGGVVIA (Aβ(35-42)). In our simulations SNQQNF, SSTTSAA, and MVGGVV form large numbers of fibrillar structures spontaneously (as in experiment). GGVVIA forms β-sheets that do not stack into fibrils (unlike experiment). The combination sequence MVGGVVIA forms less fibrils than MVGGVV, hindered by the presence of the hydrophobic residues at the C-terminal. Analysis of the simulation kinetics and energetics reveals why MVGGVV forms fibrils and GGVVIA does not, and why adding I and A to MVGGVVIA reduces fibrillization and enhances amorphous aggregation into oligomeric structures. The latter helps explain why Aβ(1-42) assembles into more complex oligomers than Aβ(1-40), a consequence of which is that it is more strongly associated with Alzheimer's disease. © 2014 Wiley Periodicals, Inc.
URI
http://hdl.handle.net/20.500.11750/3080
DOI
10.1002/prot.24515
Publisher
Wiley Blackwell
Related Researcher
  • Author Chang, Ik Soo Theoretical and Computational Biophysics Laboratory
  • Research Interests
Files:
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Collection:
Brain and Cognitive SciencesETC1. Journal Articles


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