Integrative genomic analyses combined with molecular dynamics simulations reveal the impact of deleterious mutations of Bcl-2 gene on the apoptotic machinery and implications in carcinogenesis

Abstract

Objectives: Unlike other diseases, cancer is not just a genome disease but should broadly be viewed as a disease of the cellular machinery. Therefore, integrative multifaceted approaches are crucial to understanding the complex nature of cancer biology. Bcl-2 (B-cell lymphoma 2), encoded by the human BCL-2 gene, is an anti-apoptotic molecule that plays a key role in apoptosis and genetic variation of Bcl-2 proteins and is vital in disrupting the apoptotic machinery. Single nucleotide polymorphisms (SNPs) are considered viable diagnostic and therapeutic biomarkers for various cancers. Therefore, this study explores the association between SNPs in Bcl-2 and the structural, functional, protein-protein interactions (PPIs), drug binding and dynamic characteristics. Methods: Comprehensive cross-validated bioinformatics tools and molecular dynamics (MD) simulations. Multiple sequence, genetic, structural and disease phenotype analyses were applied in this study. Results: Analysis revealed that out of 130 mutations, approximately 8.5% of these mutations were classified as pathogenic. Furthermore, two particular variants, namely, Bcl-2G101V and Bcl-2F104L, were found to be the most deleterious across all analyses. Following 500 ns, MD simulations showed that these mutations caused a significant distortion in the protein conformational, protein-protein interactions (PPIs), and drug binding landscape compared to Bcl-2WT. Conclusion: Despite being a predictive study, the findings presented in this report would offer a perspective insight for further experimental investigation, rational drug design, and cancer gene therapy.