Binding of Mammea A/AA (MA) to calf thymus DNA revealed by the ratiometric absorbance of MA in the UV-visible range molecular dynamic simulations and TD-DFT calculations

The in vitro anti-proliferative activity of MA (5,7-dihydroxy-8-(3-methylbut-2-enyl)-6-(3-methyl-1-oxobutyl)-4-phenyl[1]2H-[1]benzopyran-2-one)on a variety of cancer cells was previously demonstrated. This work strives to understand the mechanisms by which MA exerts this biological activity. Thereafter, the binding of MA to calf thymus DNA was studied by monitoring the change in the UV-visible absorbance of MA. It was found that, the response of MA to binding with calf thymus DNA is characterised by an increase in the A_S/A_L ratio of the absorbance of the longest wavelength absorption band to the shortest one, and the appearance of a new band at about 377 nm assigned to S0→S1 transition, which is red shifted as compared to free MA. From the bands ratio, the binding constant is found to be 4.3x10⁵ M^-1, indicating strong binding. The deduced binding free energy, enthalpy and entropy are -7.7 kcal/mol, -10.89 ± 0.28 kcal/mol and -54.46 ± 4 J/K, respectively, indicating that MA binds to DNA by a non-bonding Van der Waals type interactions and hydrogen bonds. Further study with classical molecular dynamics shows that MA binds to DNA by intercalation, where it is positioned between two AT base pairs. Unlike isolated MA, TDDFT calculations on ten images extracted from the MD trajectory show that, the frontier molecular orbitals of the complex are distributed over the DNA and MA. This indicates a strong stacking interaction and then explains the hypochromism and the red shift of the S0→S1 transition. The present work demonstrates the potency of MA as antitumor compound and as absorbance-based molecular probe.Communicated by Ramaswamy H. Sarma.