Molecular mechanism and binding free energy of doxorubicin intercalation in DNA

Abstract

The intercalation process of binding doxorubicin (DOX) in DNA is studied by extensive MD simulations. Many molecular factors that control the binding affinity of DOX to DNA to form a stable complex are inspected and quantified by employing continuum solvation models for estimating the binding free energy. The modified MM-PB(GB)SA methodology provides a complete energetic profile of ΔG_ele, ΔG_vDW, ΔG_polar, ΔG_non-polar, TΔS_total, ΔG_deform, ΔG_con, and ΔG_ion. To identify the sequence specificity of DOX, two different DNA sequences, d(CGATCG) or DNA1 and d(CGTACG) or DNA2, with one molecule (1 : 1 complex) or two molecule (2 : 1 complex) configurations of DOX were selected in this study. Our results show that the DNA deformation energy (ΔG_deform), the energy cost from translational and rotational entropic contributions (TΔS_tran+rot), the total electrostatic interactions (ΔG_polar-PB/GB + ΔG_ele) of incorporation, the intramolecular electrostatic interactions (ΔG_ele) and electrostatic polar solvation interactions (ΔG_polar-PB/GB) are all unfavorable to the binding of DOX to DNA. However, they are overcome by at least five favorable interactions: the van der Waals interactions (ΔG_vDW), the non-polar solvation interaction (ΔG_non-polar), the vibrational entropic contribution (TΔS_vib), and the standard concentration dependent free energies of DOX (ΔG_con) and the ionic solution (ΔG_ion). Specifically, the van der Waals interaction appears to be the major driving force to form a stable DOX–DNA complex. We also predict that DOX has stronger binding to DNA1 than DNA2. The DNA deformation penalty and entropy cost in the 2 : 1 complex are less than those in the 1 : 1 complex, thus they indicate that the 2 : 1 complex is more stable than the 1 : 1 complex. We have calculated the total binding free energy (BFE) (ΔG_t-sim) using both MM-PBSA and MM-GBSA methods, which suggests a more stable DOX–DNA complex at lower ionic concentration. The calculated BFE from the modified MM-GBSA method for DOX–DNA1 and DOX–DNA2 in the 1 : 1 complex is −9.1 and −5.1 kcal mol⁻¹ respectively. The same quantities from the modified MM-PBSA method are −12.74 and −8.35 kcal mol⁻¹ respectively. The value of the total BFE ΔG_t-sim in the 1 : 1 complex is in reasonable agreement with the experimental value of −7.7 ± 0.3 kcal mol⁻¹.