What question did this study set out to answer?

The central aim is to identify specific pathogenic non-synonymous SNPs in the KRAS gene and understand their effects on protein structure and stability.

February 12, 2026Open Access

Pathogenic KRAS variants disrupt structure and dynamics: Insights from integrated computational analyses

Key Points

The central aim is to identify specific pathogenic non-synonymous SNPs in the KRAS gene and understand their effects on protein structure and stability.
Screened 173 non-synonymous SNPs using computational workflows.
Utilized predictive analyses for pathogenicity and evolutionary conservation.
Performed molecular dynamics simulations to assess structural stability and residue flexibility.
Mapped post-translational modifications and analyzed protein-protein interactions.
Identified four high-impact variants: L79P, A130P, G138E, and F141L.
Simulations indicated significant changes in conformational stability and residue flexibility.
Altered hydrogen bonding patterns and binding energetics were observed compared to the wild type.
Variants are primarily linked to colorectal, pancreatic, and lung cancers, highlighting their clinical importance.

Abstract

Background KRAS is among the most frequently mutated oncogenes in pancreatic, colorectal, and lung cancers, yet the structural and dynamic mechanisms by which specific coding variants alter its function remain poorly understood. This study employs an extensive in-silico protocol to identify the most detrimental non-synonymous single nucleotide polymorphisms (nsSNPs) within the KRAS gene. Objective To identify and describe pathogenic non-synonymous single nucleotide polymorphisms (nsSNPs) in KRAS and elucidate their atomistic effects on structure, stability, and potential oncogenic initiation. Methods A total of 173 nsSNPs were screened operating an integrated computational workflow combining pathogenicity prediction, evolutionary conservation assay, high-resolution structural modeling, molecular docking, atomistic molecular dynamics simulations, post-translational modification mapping, and protein–protein interaction assessment. Results Four high-impact variants (L79P, A130P, G138E, and F141L) were determined as the most deleterious. Simulations revealed distinct perturbations in conformational stability (RMSD), residue flexibility (RMSF), hydrogen bonding patterns, and binding energetics compared with the wild type, signifying mutation-induced destabilization and potential impairment of KRAS regulatory function. Notably, these variants are primarily associated with colorectal, pancreatic, and lung cancers, underscoring their clinical significance. Conclusion This integrative examination provides mechanistic insightinto how specific KRAS variations may prompt oncogenic activation. The identified alterations represent high-priority targets for experimental confirmation, illuminating the power of computational techniquesin linking sequence variationand functional consequence in cancer biology.

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