Structural analysis of the Aβ(11–42) amyloid fibril based on hydrophobicity distribution

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).

Filamentous Aggregates of Tau Proteins Fulfil Standard Amyloid Criteria Provided by the Fuzzy Oil Drop (FOD) Model

“…It seems that linear propagation—which can be regarded as contrary to the emergence of a centralized hydrophobic core (as seen in globular proteins)—is a characteristic property of amyloids. A similar phenomenon can be observed in Aβ amyloids [ 39 , 40 ]. The network of hydrogen bonds that is discussed in numerous studies [ 11 , 41 ] favors this type of conformation and is thought to be associated with the linear properties of beta folds.…”

Internal force field in selected proteins

“…Our analysis underscores the distinction between globular proteins and amyloids. Previous publications highlighted differences related to distributions of hydrophobicity, identifying areas where the observed distribution opposes the theoretical model Lim et al, 2016;Dułak et al, 2019). These fragments are regarded as "amyloid seeds" -however, in the context of electrostatic and vdW interactions, they have no special properties compared to the rest of the amyloid chain.…”

Alternative Hydrophobic Core in Proteins—The Effect of Specific Synergy

“…In this way, a band micelle is obtained, which is generated by amyloid proteins. Amyloids represent a structural form with a hydrophobic core in the form of a tape running along the long axis of fibril surrounding it with better or worse matched bands with low hydrophobicity [48][49][50][51][52]. Thus, amyloids are a synergy that is different from the native form, leading to an alternative solution to the impact and presence of a polar aquatic environment.…”

“…The current analysis is to check the degree of universality of this approach including correctly folded proteins. The structure of the hydrophobic core-its degree of compliance with the idealized distribution-is determined using a model called the fuzzy oil drop model [47][48][49][50][51][52][53][54][55][56][57], in which the idealized distribution of hydrophobicity (T) is expressed using a 3D Gaussian distribution, which is spread over the body of the protein (values of the σ-x, α-y and α-z parameters are selected specifically for a given protein). On the other hand, the actual distribution of hydrophobicity (O) is assessed resulting from the distribution of so-called effective atoms (the average position of atoms included in a given amino acid) and intrinsic hydrophobicity, which is constant for a given amino acid.…”

“…The work shows that the structure of the hydrophobic core is the result of general molecular synergy expressed in the organization of the distribution of hydrophobicity which is the share of all components. This synergy is particularly evident in changes known as amyloid transformation [48][49][50][51].…”