![]() ![]() Atomistic molecular dynamics simulations were then performed and compared with the scattering data, achieving high consistency at both small and wider scattering angles ( q = 0–1.5 Å –1). X-ray scattering data were acquired at a series of solute and salt concentrations to effectively measure interleucine interactions, indicating that a major scattering peak is observed consistently at q = 0.83 Å –1. These results suggest that missense mutations affecting highly conserved amino acids with strongly hydrophobic side chains can disturb important features of the BRCA-1 protein and may play a role in breast and ovarian cancer formation.We present a joint experimental–computational study to quantitatively describe the thermodynamics of hydrophobic leucine amino acids in aqueous solution. The two most frequently observed known cancer-predisposing missense mutations in the BRCT repeats, M1775R and A1708E, conform to this pattern. In addition, missense mutations disproportionately perturb conserved amino acids with strongly hydrophobic side chains (chi(2) = 68.57, P < 0.001) and alter the strongly hydrophobic property. The results showed that missense mutations disproportionately target amino acids that are identical in all four mammals (chi(2) = 46.01, P < 0.001). ![]() A statistical model was developed, and chi(2) tests were used to determine whether missense mutations are randomly distributed throughout the BRCT repeats or whether they disproportionately target certain amino acids. It was hypothesized that amino acids conserved in evolution would be disproportionately targeted by the mutations and that conserved amino acids with strongly hydrophobic side chains would be disproportionately perturbed. A bioinformatic analysis was conducted to evaluate 246 BRCT missense mutations from high-risk breast and/or ovarian cancer patients (reported in the NIH Breast Cancer Information Core database). The COOH-terminal region of BRCA-1 encodes two BRCT repeats, which are partially conserved in mammalian species (human, dog, rat, and mouse 60% amino acid identity). Inherited missense mutations in the tumor suppressor gene, BRCA-1, may predispose to breast or ovarian cancer, but the exact effects on the protein are generally unknown. ![]()
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January 2023
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