Stabilities and conformations of Alzheimer's β-amyloid peptide oligomers (Aβ _{16 – 22} , Aβ _16–35 , and Aβ _{10 – 35} ): Sequence effects

Abstract

Previously, we have studied the minimal oligomer size of an aggregate amyloid seed and the mechanism of seed growth with a multilayer ␤-sheet model. Under high temperature simulation conditions, our approach can test the stability of possible amyloid forms. Here, we report our study of oligomers of Alzheimer's amyloid ␤-peptide ( amyloid conformation ͉ ␤-sheet ͉ double-layered sheets ͉ molecular dynamics simulation ͉ protein folding C hanges in sequence or in shape of a protein may lead to a conformational disease. Conformational diseases are typically expressed in the appearance of amyloid fibrils. Understanding amyloid seed formation and elongation at the molecular level presents a major challenge, as it may lead to novel approaches in design and therapy (1). A relatively large number of protein conformational diseases have already been identified (2). Interestingly, at least in proteins related to Alzheimer's disease, prion protein-related encephalopathies, and type II diabetes, it has been discovered that certain short sequence fragments (5-40 residues) contained within the respective proteins can form amyloids, even in isolated peptide form. The human islet amyloid polypeptide (hIAPP), a 37-residue peptide hormone, is implicated in type II diabetes. Fibrils obtained from this hormone have been observed to be toxic to human and to rat islet ␤-cells in vitro (3). Experiments have demonstrated that a hexamer of hIAPP (residues 22-27, NFGAIL) and even a pentamer (residues 23-27, FGAIL) are already sufficient for amyloid formation and cytotoxicity (4). Prion proteins also contain such amyloidogenic peptide-fragments. Several fragments of the Syrian hamster prion protein (ShPrP) have been observed to form amyloids. These include residues 109-122, 178-191, and 202-218 (5). Within these, the most highly amyloidogenic peptide is AGAAAAGA, which corresponds to ShPrP residues 113-120. This fragment is conserved in all species whose PrP sequence has been determined (5). The ␤-peptide (A␤, 42 residues) from Alzheimer's amyloid precursor protein, constitutes a particularly important example and is among the best studied amyloidogenic peptides. A key step in Alzheimer's disease involves proteolytic cleavage of A␤ (6). The fragment consisting of residues 25-35 in A␤ (GSNKGAIIGLM) has been shown to already form large ␤-sheet fibrils, essentially similar to those obtained by the full-length A␤ (refs. 7-11). Other fragments including 1-28, 16-22, and 10-35 have also been well studied (reviewed in ref.12). Although experimental data on the ␤-sheet orientation have been elusive for A␤ 25-35 (12, 13), solid state NMR experiments revealed that A␤ 16 -22 forms an antiparallel ␤-sheet (14), and that A␤ 10 -35 and the whole sequence of 1-40 form parallel ␤-sheet amyloids (15,16). Although the IR spectra of the A␤ 24 -35 amyloid indicates the existence of an antiparallel ␤-sheet (17), x-ray diffraction failed to identify an ordered ␤-crystalline in the 24-35 fragment amyloid (12, 13).That these disease-related short peptides are ...

Annular Structures as Intermediates in Fibril Formation of Alzheimer Aβ17−42

“…The proposed candidate quaternary structures contain two layers of Aβ 40 molecules stacked in either parallel or antiparallel fashion perpendicular to the fibril axis. In parallel, Ma and Nussinov 21 independently predicted that the Aβ peptide amyloid adopts a U-turn bent β-strandloop-β-strand motif, illustrating the key structural features of the salt bridge between Asp23-Lys28 and the intramolecular hydrophobic cluster between Leu17/Phe19 and Ile32/Leu34, qualitatively agreeing with the Tycko et al model 22 . Lührs et al 23 presented a 3D structure of Aβ 17-42 fibrils based on hydrogen/deuterium-exchange NMR data (Fig.…”

Peptide folding and aggregation studied using a simplified atomic model

“…Computer simulations of Aβ 16−22 systems have been performed before [44,45], and our N c = 1 and N c = 3 results can be compared with results from molecular dynamics simulations with explicit water by Klimov and Thirumalai [45]. Our results are in reasonable agreement with theirs for N c = 1, but disagree with theirs for N c = 3.…”

Failure of Aβ(1-40) amyloid fibrils under tensile loading

“…Each fibril is characterized by a beta-cross structure, deriving from the repetition of layers stacking on top of each other and stabilized by a dense hydrogen bonds network. Each layer comprises two, sequence-wise identical, U-turns (sequence: DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVV) [54,55], and is twisted by an average angle θ with respect to the nearest neighbor layers. According to the ssNMR data, the first eight residues show structural disorder [54] and the corresponding coordinates are not yet available.…”