Integrated molecular dynamics elucidation of TP53 H179 zinc-binding variants: genomic and structural characterization...

Non-Small Cell Lung Cancer (NSCLC), the most prevalent form of pulmonary malignancy, is primarily classified into lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). TP53 gene is the most frequently mutated gene across numerous cancers. p53, a metalloprotein is stabilized by a tetrahedral Zn²⁺ binding motif involving Cys176, Cys238, Cys242, and His179. The His179 site, despite its structural importance, remains underexplored.

TCGA mutational profiles were evaluated for 616 LUAD and 544 LUSC individuals. This study focuses on mutational perturbations at the His179 locus, a key residue within the protein's zinc-binding motif. Frequent substitutions at H179 (Y/R/N/L/D) were identified across LUAD and LUSC cohorts. The structural and functional ramifications of these mutations were studied using combinatorial static structural analysis and atomistic molecular dynamics simulations (MDS). Conformational trajectories were analyzed to assess alterations in protein flexibility and functionally critical regions. Binding affinity values of the protein with Zn²⁺ were also evaluated for all mutants.

C > A was the predominant single-nucleotide substitution observed, with TP53 gene mutations present in 50% of LUAD and 81% of LUSC cases. All five H179 (Y/R/N/L/D) variants exhibited distinct conformational signatures and resulted in compromised protein stability. Contact maps indicated altered residue-level interaction patterns in the mutants as compared to and the wildtype. The energy landscape of the mutants was also observed to be altered in comparison to the wildtype. Structural perturbations were evident in L1 and L2 loops, indicating that these regions are involved in mutation-induced structural plasticity.

The results observed underscore the pathogenic potential of His179 mutations within the p53 Zinc-binding motif. The findings highlight the critical role of the Zinc-binding motif in maintaining p53's conformational fidelity and suggest that specific substitutions may differentially modulate its tumor-suppressive function.