The structure of the ErbB2-pertuzumab complex

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 Alanine scaning of pertuzumab in the ErbB2-pertuzumab complex

Pertuzumab (also called 2C4, trade name Perjeta) is a monoclonal antibody used in combination with trastuzumab and docetaxel for the treatment of metastatic HER2-positive breast cancer; it also used in the same combination as a neoadjuvant in early HER2-positive breast cancer.

The structure of the ErbB2-pertuzumab complex

The calculation results indicate the range of changes in affinity for various substitutions of amino acid residues, but not the dissociation constant exactly

The results obtained for proteins with a known three-dimensional structure:

1.Determination of the stability of protein complexes with point substitutions of amino acid residues taking into account the three-dimensional structure of the biocomplex, based on the introduced criterion: the condition number of pairwise potential energy of electrostatic interaction of amino acid residues.

2.The range of changes in the affinity of the dimeric complex will be obtained at each substitution. The biophysical approach developed in the article allows one to qualitatively determine key amino acid residues when interacting two polypeptide chains, as well as to estimate the range of Kd change when replacing key amino acid residues in peptides when they are bound to the target protein. Thus, we can predict the stability of protein complexes, qualitatively determine the dissociation constant, synthesize peptides with a given dissociation constant to various proteins, while allowing to increase the selectivity of peptides, increasing affinity for one protein and decreasing to others, which is an important condition for improving peptide therapy.

3. The potential energy values of the potential energy of the interaction between all amino acid residues of one protein and amino acid residues of another protein at each substitution

4. Differential Entropy Change Values for Each Change. When inserted amino acid residue in a hydrophobic pocket consisting of other amino acid residues inside the pocket with the great probability to stay amino acid residue, which has a change in entropy (H, where H is entropy), as well as the difference between the mean square deviation (√D, where D is variance) for this replacement amino acid residue and standard deviation amino acid residue of wild type protein in a hydrophobic pocket will be minimal. It should be noted that √D correlates with lg(cond(W)), which in this formulation of the problem characterizes the stability of the biological complex.

5. The value lg(cond(w)) at each replacement. The stability criterion of the protein complex (lg(cond(W)) of pairwise electrostatic interaction of the potential energy of amino acid residues allows us to estimate the range of variation of Kd values and indicate which mutations in peptides will lead to an increase/decrease in the stability of the biological complex when they are bound to proteins. Thus, before conducting a costly, time-consuming experiment, when it is necessary to synthesize a highly selective peptide, which will be characterized by high affinity for one protein and low affinity for another protein, then the method developed by us will minimize the number of experiments to search for such a peptide by theoretical calculation of a given range for high and low Kd values.

6.Three-dimensional graph of the potential energy of electrostatic interaction between two wild-types proteins. Maps of potential energy of electrostatic interaction of amino acid residues of proteins involved, which allow visualizing the nature of the formation of a protein complex, identifying the maxima and minima of potential energy between amino acid residues of two proteins and identifying key amino acid residues that account for the maximum values of potential energy. Particular attention is paid to the nature of the interacting amino acid residues (hydrophobic, hydrophilic, charged). The analysis of interacting proteins was carried out taking into account the three-dimensional structure, where areas with the highest potential energy of electrostatic interaction were identified.

The customers can make their wishes and changes to the order.The customer will receive a graphical representation of the change in the range of affinity for the subsequent substitution of amino acid residues for alanine.

The order price depends on the applied calculation accuracy: 85% or 89%

Alanine scan with 85% computational accuracy —716 Euro. All materials will be provided after 10 business days after 100% payment

Alanine scan with 89% computational accuracy —1190 Euro. All materials will be provided after 15 business days after 100% payment

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