Solution structure of the Alzheimer amyloid β‐peptide (1–42) in an apolar microenvironment

Abstract

The major components of neuritic plaques found in Alzheimer disease (AD) are peptides known as amyloid β‐peptides (Aβ), which derive from the proteolitic cleavage of the amyloid precursor proteins. In vitro Aβ may undergo a conformational transition from a soluble form to aggregated, fibrillary β‐sheet structures, which seem to be neurotoxic. Alternatively, it has been suggested that an α‐helical form can be involved in a process of membrane poration, which would then trigger cellular death. Conformational studies on these peptides in aqueous solution are complicated by their tendency to aggregate, and only recently NMR structures of Aβ‐(1–40) and Aβ‐(1–42) have been determined in aqueous trifluoroethanol or in SDS micelles. All these studies hint to the presence of two helical regions, connected through a flexible kink, but it proved difficult to determine the length and position of the helical stretches with accuracy and, most of all, to ascertain whether the kink region has a preferred conformation. In the search for a medium which could allow a more accurate structure determination, we performed an exhaustive solvent scan that showed a high propensity of Aβ‐(1–42) to adopt helical conformations in aqueous solutions of fluorinated alcohols. The 3D NMR structure of Aβ‐(1–42) shows two helical regions encompassing residues 8–25 and 28–38, connected by a regular type I β‐turn. The surprising similarity of this structure, as well as the sequence of the C‐terminal moiety, with those of the fusion domain of influenza hemagglutinin suggests a direct mechanism of neurotoxicity.

In silico study of amyloid β-protein folding and oligomerization

“…We use the mostly ␣-helical A␤ monomer conformation from the Protein Data Bank (36) as a starting conformation (37,38). We place 32 well separated peptides into our box and then perform a DMD simulation at a high temperature (T ϭ 2.0 E HB ͞k B ), recording the 32-peptide conformation every 10,000 simulation steps.…”

Atomic and Dynamic Insights into the Beneficial Effect of the 1,4-Naphthoquinon-2-yl-l-tryptophan Inhibitor on Alzheimer’s Aβ1–42 Dimer in Terms of Aggregation and Toxicity

“…The initial coordinates of Aβ1−42 monomer were taken from model 1 of PDB entry 1IYT. 63 This conformation observed by NMR in an apolar environment is characterized by two α-helices spanning residues 8−25 and 28−39 ( Figure 1B). The monomer with the N-and C-termini treated as NH 3 + and COO − was then replicated and translated to obtain the initial dimer structures in a parallel orientation with no interchain atomic distances of <10 Å.…”

The Alzheimer’s β amyloid (Aβ1–39) monomer in an implicit solvent

“…On the other hand, NMR results show conformations varying from ␣-helical structure in a nonpolar solution 8 to disordered N-terminal and C-terminal tails with consistent turn regions as determined by electrospray mass spectroscopy and implicit solvent MD. 26,27 The side chain of most hydrophobic residues found in the shorter arm point outward, providing a hydrophobic platform for an association between A␤ monomer. This is consistent with the simulation by Tarus et al 28 of dimerization of A␤ 10-35 using umbrella sampling and MD.…”

“…Ma and Nussinov 11 suggested that at high temperature fragments A␤ [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35] and A␤ form a strand-loop-strand structure with parallel ␤ sheet, with an interior salt bridge between Asp23 and Lys28 residues as a major element of the fibril structure. On the other hand, computational studies using coarse-grained as well as atomistic atom models suggest the formation of antiparallel ␤ sheets by A␤ [16][17][18][19][20][21][22] subpeptides.…”