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The developed software, the applied calculation principles and the result of its experimental testing are presenting in this study. The procedure for modeling is based on widespread model of behavior of protein molecules mainly contacting with water. Protein in water is a carrier of electrostatic charges, which are result of oxidation-reduction reaction. The values of these charges depend on a medium pH value and isoelectric point of amino acid residues, which bear charges. Because of difference of isoelectric points of amino acid residues the alteration of pH value changes not only electrostatic intensity, but also the geometry of the field. This protein property is used by many viruses to infect the cell by metabolic pathway. This pathway of infection is used by such dangerous viruses as tick-born encephalitis, Influenza viruses. Thorough consideration of the model brings to light that the geometry of electrostatic field is also affected by rugged surface of protein molecule. Curve boundaries of different dielectrics, protein and water, distort electrostatic field with so called polarization effects. These effects play an important role in the interactions of contacting protein molecules or molecular domains. Since almost all functional proteins, including virus envelope ones, have domain structure the polarization effects make a significant contribution to their interactions and transformations. Such influence of the protein molecule form on the electrostatic forces can explain the surprising facts that the replacements of amino acid residues in the protein structure, which don't alter neither charge nor hydrophilic value, dramatically alter biological properties of viruses, strengthening or attenuating their activities. Since globular proteins contain over thousand of atoms, which have a sufficiently dense collocation in macromolecule, such molecules can be described as continuum media. On the other hand, the interactions involving only a few atoms should be described at an atomic level, because there is an appearance of influence of individual properties of atoms. Linear characteristic sizes of polarization effects are located in an intermediate region, where both atomic description of biological macromolecules and their description as continuum objects are applicable. This fact gives an advantage consisting in that there is possibility to describe with two different models. Their combination takes into account the all significant details of interaction. The software calculation procedure uses the special algorithm for calculation of polarization effects, which was created using the solution of the special model problem. The solution was obtained by numerical means and then transformed into analytic form for the subsequent application. The software was used for studying the process of the activation of viral envelope proteins, which has the mechanism attributable to viruses of HIV-1 type and Influenza A type. This process is an irreversible protein transformation from a metastable native state to fusogenic state. The native form of the protein is a trimer of globular units. Inner domains of trimer have such structure that the contact with water causes the formation a long helix. The outer domains insulate inner ones from water molecules and hold them in a native state. During process of the protein transformation the outer domains expand and create conditions for a formation of alpha-helix secondary structure of inner regions of polypeptide chains, which, during the formation, relocate to the top of viral protein, where they can root into the cell membrane causing the fusion of virus and cell membranes and subsequent penetration the virus genetic material into the cell cytoplasm. The expanding of the outer domains can be started by different means depending on virus type. In case of HIV-1 type the activation process is initiated by an interaction of HIV-1 gp41 with chemokin co-receptor, which occurs after the binding of HIV-1 gp120 envelope protein with CD4 cell receptor. Because of an immediate proximity of participating units the polarization effects make a significant contribution to these multiple receptor interactions. In case of Influenza virus the expanding of the outer domains is initiated by their protonation. It occurs after the target cell captures a virus particle into an endosome. In order to activate hydrolases for degradation of the virus particle the cell decreases pH value in the endosome, protonating outer domains and provoking the activation of viral proteins. The experimental testing for case of Influenza virus was carried out using the technique of measure of kinetics of virus-induced hemolysis. The results of modeling showed a good accordance with the data obtained experimentally. |
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