Молодежный инновационный вестникМолодежный инновационный вестник2415-7805Федеральное государственное бюджетное образовательное учреждение высшего образования "Воронежский государственный медицинский университет имени Н.Н. Бурденко" Министерства здравоохранения Российской Федерации7309Conference ProceedingsANALYSIS OF BINDING AFFINITY AND CHANGES IN THE INTERACTION INTERFACE BETWEEN THE R87W MUTANT TYPE OF P16INK4A AND CDK6AndreevPavelpuandreev@vrngmu.ruhttps://orcid.org/0000-0002-4123-9347SvetlanaStikinastikina.pedfak@yandex.ruhttps://orcid.org/0000-0002-3511-3553MakhinaVeraveramakhina06@gmail.comhttps://orcid.org/0000-0003-4344-9951300620221127321502202211032022Copyright © 2022, Andreev P., Svetlana S., Makhina V.2022<p><span class="VIiyi" lang="en"><span class="JLqJ4b" data-language-for-alternatives="en" data-language-to-translate-into="ru" data-phrase-index="0" data-number-of-phrases="1">Relevance. The human CDKN2A gene encoding the p16INK4A protein is located at locus 9 of the chromosome, which is subject to a high mutagenesis rate. Several tens of missense mutations have been described, accompanied by the replacement of one amino acid residue in the p16 INK4A polypeptide chain, as a result of which the binding activity of the protein against CDK4 is reduced. At the same time, the effect of amino acid substitutions on the binding affinity of p16INK4A with its dominant CDK6 ligand requires further clarification in light of the critical role of the p16/CDK6 complex in the regulation of mitotic activity in eukaryotic cells. In the present work, the biological consequences of replacing arginine at position 87 of the polypeptide chain with tryptophan are considered in the context of the affinity of the p16INK4A mutant type for CDK6. Target. Analysis of changes in the binding affinity and interaction interface of the R87W mutant type p16INK4A protein with the predominant cyclin-dependent kinase CDK6. Materials and methods. Structural and functional consequences of replacing arginine with tryptophan at position 87 of the p16INK4A protein polypeptide chain in the context of the formation of a molecular complex with cyclin-dependent kinase CDK6 were analyzed using structural bioinformatics and computer biology methods. Results. It was found that the replacement of the R87W amino acid residue is accompanied by changes in the secondary conformation, physicochemical properties of p16INK4A, and also in the interface of its interaction with CDK6. The predicted G values of binding and dissociation constants of p16/CDK6 -9.94 kcal/mol and 5.12e-08 M, respectively, while the predicted values of G binding and dissociation constants of the mutant type p16R87W/CDK6 -9.49 kcal/mol and 1.10 e-07M respectively. Conclusion. As a result of the pyrimidine pyrimidine transition at position 21971100 of human autosome 9, which corresponds to the E2 exon of the CDKN2A gene, a missense mutation occurs, the essence of which is a nonsynonymous replacement of cytosine with thymine in the coding chain of the gene, as a result of which the complementary nucleotide adenine appears in the template chain . Thus, the elongation of the primary transcript is accompanied by the formation of a single tryptophan-coding codon UGG. Ultimately, R87W is replaced in the polypeptide chain of the p16INK4A protein, leading to changes in its secondary conformation, physicochemical properties, and energy profiles of the interaction interface with CDK6. The results of this in silico study demonstrate a decrease in the binding affinity of the R87W mutant type tumor suppressor p16INK4A to the cyclin-dependent kinase CDK6, illustrating the importance of conservation of the amino acid context in the region of the pre-loop turn of the ascending -helix 3 of the ankyrin repeat in light of the inhibition of the G0/G1 and G1/S transitions by the p16INK4A protein.</span></span></p>CDKN2Ap16single nucleotide polymorphismmutationtransitnon-synonymous substitutionregulation of proliferative activityCDKN2Ap16однонуклеотидный полиморфизммутациятранзициянесинонимичная заменарегуляция пролиферативной активности[Hamosh A, Amberger JS, Bocchini C, Scott AF, Rasmussen SA. Online Mendelian Inheritance in Man (OMIM®): Victor McKusick's magnum opus. Am J Med Genet A. 2021;185(11):3259-3265. doi:10.1002/ajmg.a.62407][Zhao R, Choi BY, Lee MH, Bode AM, Dong Z. Implications of Genetic and Epigenetic Alterations of CDKN2A (p16(INK4a)) in Cancer. 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