Abstract
The structure of the Aβ(11–42) amyloid available in PDB makes possible the molecular analysis of the specificity of amyloid formation. This molecule (PDB ID 2MVX) is the object of analysis. This work presents the outcome of in silico experiments involving various alternative conformations of the Aβ(11–42) sequence, providing clues as to the amylodogenecity of its constituent fragments. The reference structure (PDB) has been compared with folds generated using I-Tasser and Robetta—the strongest contenders in the CASP challenge. Additionally, a polypeptide which matches the Aβ(11–42) sequence has been subjected to folding simulations based on the fuzzy oil drop model, which favors the production of a monocentric hydrophobic core. Computer simulations yielded 15 distinct structural forma (five per software package), which, when compared to the experimentally determined structure, allow us to study the role of structural elements which cause an otherwise globular protein to transform into an amyloid. The unusual positions of hydrophilic residues disrupting the expected hydrophobic core and propagating linearly along the long axis of fibril is recognized as the seed for amyloidogenic transformation in this polypeptide. This paper discusses the structure of the Aβ(11–42) amyloid fibril, listed in PDB under ID 2MXU (fragment od Aβ(1–42) amyloid).
Highlights
The volume of published papers which focus on amyloids is rapidly growing
Analysis of amyloid structures has to deal with the dynamics and flexibility of proteins, which must be capable of specific interactions with their intended ligands and substrates [3, 4]
Much progress has recently been made owing to introduction of solid-state NMR [10]
Summary
Literature reviews [1] provide an up-to-date overview of current trends in protein misfolding research. This broad field encompasses various specific issues, such as the genetic underpinnings of amyloidogenesis and molecular studies [2], including protein folding simulations. Analysis of amyloid structures has to deal with the dynamics and flexibility of proteins, which must be capable of specific interactions with their intended ligands and substrates [3, 4]. While traditional NMR is a useful tool, it requires soluble molecules [6], and that presents a problem when studying the pathogenicity of amyloids [7,8,9]. One example is the elucidation of the structure of Aβ(1–42), and
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