In silico and structure-based evaluation of deleterious mutations identified in human Chk1, Chk2, and Wee1 protein...

Area of Science:

• Molecular Biology
• Genetics
• Bioinformatics

Background:

• Checkpoint kinases (Chk1, Chk2, Wee1) are vital for maintaining genomic integrity during DNA damage response.
• Cancer-associated mutations in these kinases can disrupt normal cellular functions.
• Understanding the functional impact of these mutations is crucial for therapeutic development.

Purpose of the Study:

• To identify and characterize deleterious variants in human Chk1, Chk2, and Wee1 using in silico and structure-based approaches.
• To analyze the effects of these mutations on protein folding patterns and structural integrity.
• To identify potential therapeutic targets based on the identified mutations.

Main Methods:

• Retrieved variants of uncertain significance for Chk1, Chk2, and Wee1 from databases.
• Employed multiple in silico prediction servers (Interpro, I-Mutant 3.0, Consurf, TM-align) to assess variant pathogenicity.
• Utilized sequence analysis (Clustal Omega) and 3D structure alignment (TM-align).
• Performed molecular dynamics simulations to evaluate folding patterns and structural integrity of wild-type and mutant proteins.

Main Results:

• Identified 36 pathogenic variants in Chk1, 250 in Chk2, and 29 in Wee1 using in silico tools.
• Found 25 highly conserved, deleterious mutations in Chk1, 189 in Chk2, and 14 in Wee1 that affect protein structure and function.
• Molecular dynamics simulations revealed significant differences in folding patterns between wild-type and mutant proteins.

Conclusions:

• The study successfully identified numerous pathogenic and deleterious mutations in Chk1, Chk2, and Wee1.
• These mutations significantly influence protein structure and function, potentially contributing to cancer development.
• The identified mutations represent potential targets for novel therapeutic interventions and improved clinical management strategies.