Folding Landscapes of the Alzheimer Amyloid-β(12-28) Peptide

Baumketner, Andrij; Shea, Joan–Emma

doi:10.1016/j.jmb.2006.07.032

Cited by 72 publications

(92 citation statements)

References 64 publications

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“…To reach these conformations, A␤40 has to refold its central hydrophobic cluster segment L17-F20. and simulations in our group (9,12,13) and others (19,35) on fragments and on the full-length A␤ peptide, however, indicate that the CHC is not the most structured element of the A␤ peptide. Rather, a bend involving residues E22-K28 emerges as the most structured part of the peptide.…”

Section: Discussionmentioning

confidence: 75%

Role of the familial Dutch mutation E22Q in the folding and aggregation of the 15–28 fragment of the Alzheimer amyloid-β protein

Baumketner

Krone

Shea³

2008

Proc. Natl. Acad. Sci. U.S.A.

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Amyloid fibrils, large ordered aggregates of amyloid ␤ proteins (A␤), are clinical hallmarks of Alzheimer's disease (AD). The aggregation properties of amyloid ␤ proteins can be strongly affected by singlepoint mutations at positions 22 and 23. The Dutch mutation involves a substitution at position 22 (E22Q) and leads to increased deposition rates of the A␤E22Q peptide onto preseeded fibrils. We investigate the effect of the E22Q mutation on two key regions involved in the folding and aggregation of the A␤ peptide through replica exchange molecular dynamics simulations of the 15-28 fragment of the A␤ peptide. The A␤15-28 peptide encompasses the 22-28 region that constitutes the most structured part of the A␤ peptide (the E22-K28 bend), as well as the central hydrophobic cluster (CHC) (segment 17-21), the primary docking site for A␤ monomers depositing onto fibrils. Our simulations show that the 22-28 bend is preserved in the A␤(15-28) peptide and that the CHC, which is mostly unstructured, interacts with this bend region. The E22Q mutation does not affect the structure of the bend but weakens the interactions between the CHC and the bend. This leads to an increased population of ␤-structure in the CHC. Our analysis of the fibril elongation reaction reveals that the CHC adopts a ␤-strand conformation in the transition state ensemble, and that the E22Q mutation increases aggregation rates by lowering the barrier for A␤ monomer deposition onto a fibril. Thermodynamic signatures of this enhanced fibrillization process from our simulations are in good agreement with experimental observations. Alzheimer's disease ͉ explicit water ͉ familial type ͉ molecular dynamics simulations ͉ replica exchange T he presence of amyloid fibrils in the brain is a clinical hallmark of Alzheimer's disease (AD). The fibrils consist of large ordered aggregates of amyloid-␤ (A␤) peptides, proteolytic by-products of the enzymatic cleavage of the Alzheimer amyloid precursor protein (APP). AD can be sporadic (occurring in elderly patients and characterized by a slow progression) or familial (a hereditary form characterized by early onset of the disease and aggravated severity). The majority of familial forms of AD involve single-point mutations in the 22-23 segment of the A␤ peptide. The focus of this work is on the Dutch form of AD, which involves a mutation encoded by a point substitution G to C at codon 693 of the amyloid precursor protein (APP). The result is the production of an A␤ peptide in which residue E22 is mutated to Q (E22Q mutation). Patients who have this mutation are at risk of developing cerebral amyloid angiopathy that typically leads to cerebral hemorrhage and stroke. Many in vitro experiments show that the A␤E22Q peptide aggregates much more readily than its wild-type (WT) counterpart (1-3). As a free monomer in solution, the WT A␤ peptide is for the most part unstructured with residual structure observed locally in a few regions of the primary sequence (4). The A␤ peptide can populate a variety of oligomeric species, some...

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Section: Discussionmentioning

confidence: 75%

Role of the familial Dutch mutation E22Q in the folding and aggregation of the 15–28 fragment of the Alzheimer amyloid-β protein

Baumketner

Krone

Shea³

2008

Proc. Natl. Acad. Sci. U.S.A.

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“…The first sequence (GSNKGAIIGLM) we studied corresponds to residues 25-35 of amyloid-β which is found in patients with Alzheimer's disease [23,[56][57][58]. The second sequence (KHMAGAAAAGA) corresponds to residues 110-120 of the amyloidogenic β-hairpin peptide of the Syrian hamster prion protein, H1 peptide [23].…”

Section: Secondary Structures In Amyloidsmentioning

confidence: 99%

Hydrophobic interactions in the formation of secondary structures in small peptides

2011

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Effects of the attractive and repulsive parts of hydrophobic interactions on α helices and β sheets in small peptides are investigated using a simple atomic potential. Typically, a physical spatial range of attraction tends to favor β sheets, but α helices would be favored if the attractive range were more extended. We also found that desolvation barriers favor β sheets in collapsed conformations of polyalanine, polyvaline, polyleucine, and three fragments of amyloid peptides tested in this study. Our results provide insight into the multifaceted role of hydrophobicity in secondary structure formation, including the α to β transitions in certain amyloid peptides.

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“…12 A useful alternative are computational methods, particularly, molecular dynamics ͑MD͒ simulations, which can probe the details of A␤ amyloid formation at all-atom resolution. 23,24 Several studies have explored the conformational properties of A␤ 1-40 monomers 25,26 and its fragments [27][28][29] as well as fibril growth and stability. [30][31][32] The full-length A␤ 1-40 was shown to have several structured regions, including short ␤-strands, helices, and ␤-turns, in generally random coil-like ensemble of conformations.…”

Section: Introductionmentioning

confidence: 99%

Globular state in the oligomers formed by Aβ peptides

Kim

Takeda

Klimov

2010

The Journal of Chemical Physics

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Replica exchange molecular dynamics and implicit solvent model are used to study two oligomeric species of A␤ peptides, dimer and tetramer, which are typically observed in in vitro experiments. Based on the analysis of free energy landscapes, density distributions, and chain flexibility, we propose that the oligomer formation is a continuous transition occurring without metastable states. The density distribution computations suggest that A␤ oligomer consists of two volume regionsthe core with fairly flat density profile and the surface layer with rapidly decreasing density. The core is mostly formed by the N-terminal residues, whereas the C-terminal tends to occur in the surface layer. Lowering the temperature results in the redistribution of peptide atoms from the surface layer into the core. Using these findings, we argue that A␤ oligomer resembles polymer globule in poor solvent. A␤ dimers and tetramers are found to be structurally similar suggesting that the conformations of A␤ peptides do not depend on the order of small oligomers.

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Folding Landscapes of the Alzheimer Amyloid-β(12-28) Peptide

Cited by 72 publications

References 64 publications

Role of the familial Dutch mutation E22Q in the folding and aggregation of the 15–28 fragment of the Alzheimer amyloid-β protein

Role of the familial Dutch mutation E22Q in the folding and aggregation of the 15–28 fragment of the Alzheimer amyloid-β protein

Hydrophobic interactions in the formation of secondary structures in small peptides

Globular state in the oligomers formed by Aβ peptides

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