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<p>Breast cancer is a complex disease primarily driven by genetic mutations that disrupt crucial signaling pathways, with the <i>AKT1</i> gene playing a central role in its progression. This study explores the impact of AKT1 mutations using Whole Exome Sequencing (WES), bioinformatics, and computational modeling. Using WES, we identified and prioritized significant mutations in patient samples, specifically D3N, V337M, and D3N-E169G. Comprehensive sequence and structural analyses were conducted to understand how these mutations affect specific functional domains of the AKT1 protein. To investigate the molecular consequences, molecular docking studies were performed to assess the binding affinity of AKT1 mutations with MK2206, a known allosteric inhibitor of AKT1. The docking results revealed substantial differences in interaction energies, indicating impaired inhibitor binding due to these mutations. Additionally, molecular dynamics simulations over a 500-nanosecond trajectory provided detailed insights into the structural perturbations caused by these mutations. This integrated study, combining genomic and computational approaches, offers a comprehensive understanding of how AKT1 mutations contribute to BC pathogenesis. These findings enhance our knowledge of the molecular mechanisms underlying the disease and support the development of targeted therapies to address the altered behavior of mutated AKT1, advancing personalized treatment strategies for BC.</p>

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Theoretical investigation of AKT1 mutations in breast cancer: a computational approach to structural and functional insights

  • 期刊论文

  • 发表日期：

    2025年5月9日

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  • Balu Kamaraj,
  • George Priya Doss C

摘要

Breast cancer is a complex disease primarily driven by genetic mutations that disrupt crucial signaling pathways, with the AKT1 gene playing a central role in its progression. This study explores the impact of AKT1 mutations using Whole Exome Sequencing (WES), bioinformatics, and computational modeling. Using WES, we identified and prioritized significant mutations in patient samples, specifically D3N, V337M, and D3N-E169G. Comprehensive sequence and structural analyses were conducted to understand how these mutations affect specific functional domains of the AKT1 protein. To investigate the molecular consequences, molecular docking studies were performed to assess the binding affinity of AKT1 mutations with MK2206, a known allosteric inhibitor of AKT1. The docking results revealed substantial differences in interaction energies, indicating impaired inhibitor binding due to these mutations. Additionally, molecular dynamics simulations over a 500-nanosecond trajectory provided detailed insights into the structural perturbations caused by these mutations. This integrated study, combining genomic and computational approaches, offers a comprehensive understanding of how AKT1 mutations contribute to BC pathogenesis. These findings enhance our knowledge of the molecular mechanisms underlying the disease and support the development of targeted therapies to address the altered behavior of mutated AKT1, advancing personalized treatment strategies for BC.