Hydropathic analysis of the free energy differences in anthracycline antibiotic binding to DNA

摘要

Molecular models of six anthracycline antibiotics and their complexes with 32 distinct DNA octamer sequences were created and analyzed using HINT (Hydropathic INTeractions) to describe binding. The averaged binding scores were then used to calculate the free energies of binding for comparison with experimentally determined values. In parsing our results based on specific functional groups of doxorubicin, our calculations predict a free energy contribution of -3.6 ± 1.1 kcal mol~(-1) (experimental -2.5 ± 0.5 kcal mol~(-1)) from the groove binding daunosamine sugar. The net energetic contribution of removing the hydroxyl at position C9 is -0.7 ± 0.7 kcal mol~(-1) (-1.1 ± 0.5 kcal mol~(-1)). The energetic contribution of the 3' amino group in the daunosamine sugar (when replaced with a hydroxyl group) is -3.7 ± 1.1 kcal mol~(-1) (0.7 ± 0.5 kcal mol~(-1)). We propose that this large discrepancy may be due to uncertainty in the exact protonation state of the amine. The energetic contribution of the hydroxyl group at C14 is +0.4 ± 0.6 kcal mol~(-1) (0.9 ± 0.5 kcal mol~(-1)), largely due to unfavorable hydrophobic interactions between the hydroxyl oxygen and the methylene groups of the phosphate backbone of the DNA. Also, there appears to be considerable conformational uncertainty in this region. This computational procedure calibrates our methodology for future analyses where experimental data are unavailable.