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Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
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Computational and structural based approach to identify malignant nonsynonymous single nucleotide polymorphisms

Rahatul Islam1, Mashiur Rahaman1, Hammadul Hoque1

  • 1Department of Genetic Engineering and Biotechnology, School of Life Sciences, Shahjalal University of Science and Technology, Sylhet, Bangladesh.

Plos One
|November 4, 2021
PubMed

Insights

This study identified highly malignant mutations in Cyclin-dependent kinase 4 (CDK4), linked to cancer progression. The G15S mutation was found to be the most destabilizing to the CDK4 protein structure and function.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Genetics

Background:

  • Cyclin-dependent kinase 4 (CDK4) is crucial for cell cycle G1 phase progression.
  • Aberrant CDK4 activity, driven by missense mutations and nsSNPs, contributes to various cancers, including melanoma, lung, and breast cancer.
  • Understanding the impact of these mutations is vital for cancer research and therapeutic development.

Purpose of the Study:

  • To computationally identify and characterize highly malignant missense mutations in CDK4.
  • To assess the functional impact of these mutations on protein structure, stability, and drug binding.
  • To compare the destabilizing effects of identified CDK4 variants.

Main Methods:

  • Utilized computational algorithms to analyze nsSNPs from the dbSNP database for CDK4.
  • Predicted the pathogenicity of missense mutations.
  • Employed molecular dynamic simulations to evaluate protein stability and binding interactions with ATP and ribociclib.

Main Results:

  • Identified G15S, D140Y, and D140H as highly malignant CDK4 missense mutations from 239 nsSNPs.
  • These mutations showed altered binding motifs for the CDK4 inhibitor ribociclib and ATP.
  • Molecular dynamic simulations indicated G15S is more destabilizing to CDK4 than D140Y and D140H.

Conclusions:

  • The G15S, D140Y, and D140H mutations represent significant threats to CDK4 function and protein integrity.
  • The G15S mutation exhibits a pronounced destabilizing effect on CDK4.
  • These findings highlight potential therapeutic targets and inform strategies for inhibiting oncogenic CDK4 variants.

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