Exploring the mechanism of C473D mutation on CDC25B causing weak binding affinity with CDK2/CyclinA by molecular dynamics study.

CDC25B belongs to the CDC25 family, and it plays an important part in regulating the activity of CDK/CyclinA. Studies have shown that CDC25B is closely related to cancer development. When CYS473 on CDC25B is mutated into ASP, the affinity between CDC25B and CDK2/CyclinA weakens, and their dissociation speed is greatly improved. However, the mechanism by which the CDC25B mutant weakens its binding to CDK2/CyclinA is unclear. In order to study the effect of CDC25B mutants on CDK2/CyclinA substrates, we constructed and verified the rationality of the CDC25B:CDK2/CyclinA system and CDC25B:CDK2/CyclinA system and conducted molecular dynamics (MD) simulation analysis. In the post-analysis, the fluctuations of residues ARG488-SER499, LYS541-TRP550 on CDC25B and residues ASP206-ASP210 on CDK2 were massive in the mutant CDC25B:CDK2/CyclinA system. And the interactions between residue ARG492 and residue GLU208, residue ARG544 and residue GLU42, residue ARG544 and TRP550 were weakened in the mutant CDC25B:CDK2/CyclinA system. The results showed that when CYS473 on CDC25B was mutated into ASP473, the mutant CDC25B:CDK2/CyclinA system was less stable than the wild-type CDC25B:CDK2/CyclinA system. Finally, active site CYS473 of CDC25B was speculated to be the key residue, which had great effects on the binding between CDC25B and CDK2 in the CDC25B:CDK2/CyclinA system. Consequently, overall analyses appeared in this study ultimately provided a useful understanding of the weak interactions between CDC25B and CDK2/CyclinA.Communicated by Ramaswamy H. Sarma.