Brownian dynamics simulations of DNB-ligand interactions: A theoretical study on the kinetics of DAPI-DNA complexation

Diffusion of DAPI (4',6-diamidino-2-phenylindole) to its DNA binding site d(AATT) is simulated by Brownian dynamics. The simulations are performed on all atom x-ray structures of the molecules with systematic intermolecular forces and hydrodynamic interactions. The roles of hydrodynamic and intermolecular forces in steering the drug to DNA and orienting it for binding are examined. The exclusion of hydrodynamic interactions lead to high values of rate constants but they seem to have only a minor effect on steering the drug to the right site. Intermolecular forces dramatically increase the encounter rate. The simulated rate constant for specific association including all interactions compares well with experiment. This study representing the DNA-ligand system at the atomic level in a Brownian dynamics simulation is the first of its kind and will hopefully pave the way for understanding mechanistic issues involved in complexation and developing docking algorithms based on Brownian dynamics. (C) 1998 Elsevier Science B.V.