In-silico screening of cancer associated mutation on PLK1 protein and its structural consequences
The Polo-like kinases (Plks) are a conserved subfamily of serine-threonine protein kinases that have significant roles in cell proliferation. The serine/threonine protein kinases or polo-like kinase 1 (PLK1) exist in centrosome during interphase and is an important regulatory enzyme in cell cycle progression during M phase. Mutations in mammalian PLK1 were found to be over expressed in various human cancers and it is disrupting the binding ability of polo box domain with target peptide. In this analysis we implemented a computational approach to filter the most deleterious and cancer associated mutation on PLK1 protein. We found W414F as the most deleterious and cancer associated by Polyphen 2.0, SIFT, I-mutant 3.0, PANTHER, PhD-SNP, SNP&GO, Mutpred and Dr Cancer tools. Molecular docking and molecular dynamics simulation (MDS) approach was used to investigate the structural and functional behavior of PLK1 protein upon mutation. MDS and docking results showed stability loss in mutant PLK1 protein. Due to mutation, PLK1 protein became more flexible and alters the dynamic property of protein which might affect the interaction with target peptide and leads to cell proliferation. Our study provided a well designed computational methodology to examine the cancer associated nsSNPs and their molecular mechanism. It further helps scientists to develop a drug therapy against PLK1 cancer-associated diseases.
molecular dynamics simulations flexibility plk-1 protein