Inhibition of Amyloid Plaque Formation

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Inhibition of Amyloid Plaque Formation


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Based on the developed by us concept, we propose a method of inhibiting amyloid peptides. The concept was based on experimental data on the characteristics of the formation of high molecular weight structural amyloid peptides. For the first time, a new method was proposed that explains the formation of high-molecular-weight amyloid structures from the point of view of the stability of amyloid complexes. We used the available experimental and clinical data, which investigated the ability of amyloid peptides with hereditary mutations to form amyloid plaques, high molecular weight structures and found that some mutations increase the tendency of amyloid peptides to aggregate and form amyloid plaques, while other mutations in amyloid peptides, on the contrary, led to noticeable reduction of detrimental effects on the body in the form of the formation of amyloid plaques and high molecular weight structures.


We concluded that the dimers of mutant amyloids form stable and unstable dimeric complexes. If the dimeric complex is stable, then the formation of high molecular weight structures was much slower. This was due to the fact that the stable amyloid peptides were in no hurry to enter into chemical reactions with other amyloid peptides to achieve equilibrium.
It remained to solve the question: how will we determine the stability of the dimeric complex.

Let me remind you that since 2015 our company has been dealing with the issues of the stability of protein compounds. We introduced a numerical stability criterion for protein dimers; this value is the condition number of the matrix of potential energy of pairwise electrostatic interaction between two proteins. The higher this number, the more unstable the biological complex. We calculated the stability values for the known dimeric amyloid complexes taking into account mutations and obtained a numerical stability value for each dimer, which was presented in the form of a graph. Higher values indicate a lower stability value and vice versa. Our goal is the identification of dimeric amyloid complexes, which would be characterized as sufficiently stable dimeric complexes. One of the peptides in the dimer complex will be exactly the amyloid peptide, and the second companion we have to find. The second partner in the dimer complex will be an inhibitor based on the amino acid sequence.

How can we get such an amino acid sequence?

We are going to get amino acid sequences that are inhibitors of the formation of amyloid oligomers from the accumulated experimental base for the study of Alzheimer’s disease.

The model we developed allows us to significantly modify the existing three-dimensional structures of amyloid peptides by introducing mutations into one or both peptides at once and to determine the stability of the resulting dimeric complex

Since the amyloid peptide contains an average of 40 amino acid residues, and a total of 20 amino acid residues, then sorting out each amino acid residue for the next would result in 600 variants, but there is a simpler, more reliable, and shorter way.


In this paper, stability will be evaluated dimeric complexes by creating a calibration scale that will characterize the stability value of the formed dimers with the participation of Aβ peptides with various missense mutations. As criteria for determining stability dimeric complex, we will use:

  1. A measure of the change in entropy (H).
  2. The condition number of the matrix, the elements of which are the potential energies of electrostatic interaction between pairwise taken amino acid residues of proteins. In this physical
    statement of the problem it will characterize the degree
    stability of the biological complex configuration.
    Moreover, to select a more stable biochemical compound between proteins, we select the matrix potential energy of electrostatic interaction with the lowest value lgcond (w) [8–10].

This work consists of several parts. The first part of the work is devoted to the derivation of the formula for calculating differential entropy for the case of a normal distribution and the determination of its measure of change.
The second part of the paper presents the results of numerical calculations. In conclusion, the main findings

Since the method presented in the article concerns a new understanding in a stable of peptide amyloids, we present a site of such an amyloid peptide ABeta (11−42), which corresponds to the length of the amino acid sequence of the three-dimensional structure from the PDB database: 2MXU. Figure 1. shows the amino acid sequence of AB (11–42) peptide indicating missense mutations (see table 1), which entail various biological and pathophysiological effects in the human body

an amyloid peptide ABeta (11−42), which corresponds to the length of the amino acid sequence of the three-dimensional structure from the PDB database: 2MXU.

Amino acid sequence of the Abeta (11-42) peptide indicating missense mutations. The numbering of amino acid residues of the peptide is also given, as well as the numbering of amino acid residues relative to the APP precursor protein

Amino acid sequence of the Abeta (11-42) peptide indicating missense mutations. The numbering of amino acid residues of the peptide is also given, as well as the numbering of amino acid residues relative to the APP precursor protein

The authors of the article used the well-known 3-dimensional structure from the PDB base: 2MXU. Of the entire set of peptides listed in it, only two polypeptide chains of amyloid peptides were left. Next, the potential energy of the electrostatic interaction between the amino acid residues was calculated. two amyloid peptides taking into account the three-dimensional structure and a matrix of potential energy of electrostatic interaction between two amyloid peptides wtA Beta (11−42) and a three-dimensional map of the potential energy of electrostatic interaction was constructed, see. 2. Moreover, the region of the C – end, taking amino acid residues I41 (ILE41) and A42 (ALA42) will be considered separately

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Based on experimental data on missense mutations and their biological effect, we introduced a dividing line at the level of 5.53, which will separate mutations in peptides, leading to enhanced formation of structures more high order from mutations in AB peptides with reduced ability to form high molecular weight structures. When choosing the value of 5.53, the two threshold values ​​were the interactions of wild type AB peptides; the values ​​of which log (cond (w)) amounted to 5.5372 and the interaction of two mutant forms of the AB K16N peptide (LYS16ASN), the dimeric form of which does not entail toxic effects on the human body. In this case, the value of lg (cond (w)) was 5.5264. The dashed line in the graphs indicates the value obtained by the interaction of the peptides [wtAB] 2. Two vertical arrows from the line at the level of 5.53 indicate the direction in the range of values ​​characterized by a lower degree of stability of dimeric complexes (up arrow) and more a high degree of stability of dimeric complexes (down arrow). This gradation of values ​​was obtained and tested for a 3-dimensional complex from the PDB database: 2MXU

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