Molecular dynamic and quantum mechanics study of drug recognition for the extremity of DNA G-quadruplex groove.

Human DNA G-quadruplex has been an attractive drug target for cancer therapeutic intervention. Especially the G-quadruplex groove has been paid growing attention to because of its selectivity. In this work, molecular dynamics (MD) simulations of the complexes of parallel G-quadruplexes ([d(TGGGGT)] and [d(GGGGGG)]) with distamycin A (Dist-A) dimmers were performed. The characteristic of drug binding in G-quadruplex grooves was investigated. The simulations reveal the propensity of Dist-A dimmer toward the end of the groove. The electronic properties of three successive G-tetrads are estimated by density functional theory (DFT) method at the B3LYP/6-31G (d, p) level. The results show that the N3 atoms in two terminal G-tetrads possess more negative charges than it in the middle G-tetrad, which is one reason for driving cation ligand toward the end of groove. This study provides the factors of affecting the binding of drugs in the G-quadruplex groove and is of significance for drug design based on the structure of G-quadruplex groove. [ABSTRACT FROM AUTHOR]