Structural analysis of the Aβ(15-40) amyloid fibril based on hydrophobicity distribution

Dułak, Dawid; Banach, Mateusz; Gadzała, Małgorzata; Konieczny, Leszek; Roterman, Irena

doi:10.18388/abp.2018_2647

Cited by 18 publications

(18 citation statements)

References 34 publications

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“…We subjected it to analysis from the point of view of hydrophobicity distribution. The presented work follows upon the results presented in [12], where we single out fragments exhibiting specific deviations from the theoretical ("idealized") distribution of hydrophobicity expected in a globular protein and mathematically defined by a 3D Gaussian [13][14][15].…”

Section: Introductionmentioning

confidence: 99%

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

Roterman

Dułak

Gadzała

et al. 2019

J Comput Aided Mol Des

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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).

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Section: Introductionmentioning

confidence: 99%

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

Roterman

Dułak

Gadzała

et al. 2019

J Comput Aided Mol Des

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“…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.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Model Of Amino Acid Conformation Analysis In the Chainmentioning

confidence: 99%

Alternative Hydrophobic Core in Proteins—The Effect of Specific Synergy

et al. 2020

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Proteins with a high degree of sequence similarity representing different structures provide a key to understand how protein sequence codes for 3D structure. An analysis using the fuzzy oil drop model was carried out on two pairs of proteins with different secondary structures and with high sequence identities. It has been shown that distributions of hydrophobicity for these proteins are approximated well using single 3D Gaussian function. In other words, the similar sequences fold into different 3D structures, however, alternative structures also have symmetric and monocentric hydrophobic cores. It should be noted that a significant change in the helical to beta-structured form in the N-terminal section takes places in the fragment much preceding the location of the mutated regions. It can be concluded that the final structure is the result of a complicated synergy effect in which the whole chain participates simultaneously.

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“…The fuzzy oil drop model treats amyloids as ribbonlike micelles (in contrast to spherical micelles, which represent globular proteins) (Kalinowska et al, 2017). The presence of short fragments, whose local distribution of hydrophobicity opposes the theoretical model, results from the systemic inability of the amyloid peptide to attain a spherical conformation (Dułak et al, 2018a;Dułak et al, 2018b). This locally suboptimal distribution is compensated by the isolation of discordant fragments in the structure of a ribbon-like micelle.…”

Section: Discussionmentioning

confidence: 99%

“…The set includes titin as a representative of a class of strongly accordant proteins (Banach et al, 2014a;Banach et al, 2014b), along with several amyloids whose structures can be found in PDB. The latter facilitate the analysis of the distribution of hydrophobic, electrostatic and vdW interactions in amyloids (note that the distribution of hydrophobicity in amyloids is extensively discussed in several other publications: (Dułak et al, 2018a;Dułak et al, 2018b)). Transthyretin was selected for this study due to its strong propensity for amyloid transformation (Lim et al, 2016).…”

Section: Methodsmentioning

confidence: 99%

Internal force field in selected proteins

et al. 2019

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The fuzzy oil drop model suggests that the tertiary conformation of a protein -particularly a globular one -can be likened to a spherical micelle. During the folding process, hydrophilic residues are exposed on the surface, while hydrophobic residues are retained inside the protein. The resulting hydrophobicity distribution can be mathematically modeled as a 3D Gaussian. The fuzzy oil drop model is strikingly effective in explaining the properties of type II antifreeze proteins and fast-folding proteins, as well as a vast majority of autonomous protein domains. This work aims to determine whether similar mechanisms apply to other types of nonbonding interactions. Our analysis indicates that electrostatic and van der Waals forces do not conform to the Gaussian pattern. The study involves a reference protein (titin) which shows a high agreement between the observed distribution of hydrophobicity and the theoretical (Gaussian) distribution, a selection of amyloid structures derived from the Protein Data Bank, as well as transthyretin -a protein known for its susceptibility to amyloid transformation.

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Structural analysis of the Aβ(15-40) amyloid fibril based on hydrophobicity distribution

Cited by 18 publications

References 34 publications

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

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

Alternative Hydrophobic Core in Proteins—The Effect of Specific Synergy

Internal force field in selected proteins

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