Molecular modeling study of binding site selectivity of TQMP to G-quadruplex DNA.

Molecular dynamics (MD) simulations of four-stranded G-quadruplex DNA complexes formed by the sequence d(TTAGGG)(4) and the TQMP ligand are presented. The TQMP complex was examined both in two possible binding modes (diagonal loop and parallel loop positions). Simulations show that the G-quadruplex DNAs with two K(+) ions in the central channel are fairly stable during 30 ns MD runs in explicit water box. pi-pi stacking and ion effect were studied with DFT calculations on the minimized MD average structure. From trajectories of MD runs, the interaction of TQMP with G-quadruplex DNA is indeed shown to correspond to the two different binding modes. Free energy analysis showed that in gas phase, the interaction between TQMP and G-quadruplex DNA is mainly electrostatic. But in water medium, the TQMP ligand preferentially binds in the diagonal loop position, the selectivity being due to a complex balance between apolar and polar contributions to the complexation free energy.