Increased stability of amyloid peptides

Alzheimer's is the most common cause of dementia, a general term for memory loss and other cognitive abilities serious enough to interfere with daily life. Alzheimer's disease accounts for 60-80% of dementia cases.

The brain has 100 billion nerve cells (neurons). Each nerve cell connects with many others to form communication networks. Groups of nerve cells have special jobs. Some are involved in thinking, learning and remembering. Others help us see, hear and smell.

To do their work, brain cells operate like tiny factories. They receive supplies, generate energy, construct equipment and get rid of waste. Cells also process and store information and communicate with other cells. Keeping everything running requires coordination as well as large amounts of fuel and oxygen.

Scientists believe Alzheimer's disease prevents parts of a cell's factory from running well. They are not sure where the trouble starts. But just like a real factory, backups and breakdowns in one system cause problems in other areas. As damage spreads, cells lose their ability to do their jobs and, eventually die, causing irreversible changes in the brain.


Stabilization of amyloid peptides at the level of dimeric complexes
We have developed a method for increasing the stability of amyloid dimers in order to reduce their ability to enter into further biochemical reactions with the formation of toxic oligomers.

Numerical calculations are presented in the form of a graphical description, which clearly allows you to see an increase or decrease in the stability of dimeric amyloid complexes. Our proposed method allows us to vary the range of stability of dimeric complexes by substitutions of key amino acid residues.


Fig.1. Comparison of experimental and calculated values that characterize the stability of amyloid peptides and their ability to enter into biochemical processes (self-aggregation), depending on the substitutions performed. Upper graph a) was obtained from experimental work[*] at a concentration of 1.1 μM. The time of half completion, t1/2, for the serine mutants in comparison with the WT Aβ42 in 20 mM sodium phosphate and 200 μM EDTA at pH 8.0 is shown in the upper graph. Below them are the corresponding calculated stability data for dimeric complexes taking into account the performed substitutions. At the same time, for clarity of viewing and comparison, the reciprocal value 1/lg(cond(W)) is given. Thus, we see a relationship between the stability of dimeric modified amyloid peptides and the half-life of their self-aggregation.

We explain it this way: the more stable the dimeric complex is, the slower it will enter into new biochemical processes.

In this work, we pay special attention to the peptide with four Ser substitutions, since it shows the least tendency to aggregation, with the longest half-life. The lower graph is the calculated value; the higher the value of the inverse of 1\lg(cond(W)) lies, the more stable the biological complex. This is a dimeric complex with four substitutions of amino acid residues for Serine (Ser).
[*]- Proc Natl Acad Sci U S A 2020 Oct 13;117(41):25272-25283. doi: 10.1073/pnas.2002956117. Epub 2020 Oct 1.The role of fibril structure and surface hydrophobicity in secondary nucleation of amyloid fibrils

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.
Fig.2. Three-dimensional map of the potential energy of pairwise electrostatic interaction between two wild-type amyloid peptides (upper figure) and taking into account mutations (lower figure)
Next, we will consider the illustrative results obtained for the change in the stability of amyloid dimers taking into account various mutations in amyloid peptides.

The figures below show the numerical results obtained for various mutations and a brief description of their physical properties, which varied depending on changes in the resistance of amyloids at the level of dimeric complexes.
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Fig.3. Graph of values for stability indicator lg(cond(w)) that were obtained by considering the interaction of wild form wtABeta and interaction of mutant peptide forms mutABeta from Table 1.

The stability of biological complex is plotted in Fig. 3. The mutation names and the way the structures of a higher order are formed are indicated in the plots. A large arrow between the plots indicates the direction for values characteristic of the formation of structures with a higher molecular weight such as oligomers, protofibrils, and fibrils. A thick line at a level of 5.53 arbitrarily separates structures that tend to (the region below the line). The "FAB" designation on the plot corresponds to the stability value upo interaction of the solanezumab region with an amyloid peptide (a structure in the PDB:4XXD database) .

On the strength of experimental data on missense mutations and their biological effect, we draw a separation line at a level of 5.53 that separates mutations in peptides leading to enhanced formation of higherorder structures from mutations in ABeta peptides exhibiting a reduced capacity to form high-molecular weight structures.

Two vertical arrows pointing away from the line drawn at 5.53 indicate directions in the regions characterized by the lower (arrow up) or higher (arrow down) stability of dimer complexes. The present grading was obtained and tested for a three-dimensional complex from the PDB:2MXU database [12].

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Fig.2. Amino acid sequence of the ABeta(11–42) peptide, with
its missense mutations being indicated. AAR numbering is
given in two variants: for the peptide itself and relative to its
predecessor protein APP.
Since the method proposed in this work concerns a new insight into the stability of peptide amyloids, we will provide a fragment of such an amyloid peptide ABeta (11–42) that corresponds to the length of amino acid sequence of a three-dimensional structure from the PDB:2MXU database [5]. Figure 2 shows the amino acid sequence of ABeta (11–42) peptide in which missens mutations that lead to different biological and pathophysiological changes in the human body are indicated [23]. Figure 2. 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

Read more about the proposed methods

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