Predicting structural and spectral properties in a Minor-Groove binder with classical and quantum mechanical calculations

Regulated DNA-binding ligands can be employed to design fluorescent probes and new drugs for promising chemical and biological applications. However, predicting the binding affinities of DNA ligands based on energy and geometry remains a challenge. In this work, combined molecular docking, molecular dynamics (MD) simulation, and generalized energy-based fragmentation (GEBF) approaches were performed to predict the three binding complexes between DNA and fluorescent or drug molecules. The GEBF binding energy calculation finds that the predicted optimal complexes would agree with the experimental ones in a minor-groove binder, which is more accurate and effective than molecular mechanics and semi-empirical quantum mechanics. The binding site of the water molecule around DAPI-DNA, which forms hydrogen bond networks with the DAPI ligand, can also be predicted with the GEBF method. The result show that the predicted absorption spectra are closely match the experimental measures when considering the solvent, electrostatic, and polarization interactions. Thus, the theoretical calculations using docking, MD simulations, and GEBF methods can be applied to predict the binding modes and sites of DNA ligands, suggesting that it is helpful for virtual screening and designing new small ligands to recognize DNA with various applications.