Monte Carlo docking of protein-DNA complexes: incorporation of DNA flexibility and experimental data.

A Monte Carlo simulation program (MONTY) has been developed to dock proteins onto DNA. Protein and DNA interact via square-well potentials for hydrogen bond and van der Waals interactions. The effect of the inclusion of DNA flexibility and experimentally derived restraints has been tested on members of the helix-turn-helix family of DNA binding proteins. Unwinding and bending the DNA double helix improves the number of correctly retrieved hydrogen bonds in simulations starting from the 434 cro protein monomer complexed with a standard B-DNA OR1 half-site. Agreement with phosphate ethylation interference and mutagenesis data is rewarded with energy bonuses. This protocol was tested on protein-DNA complexes of 434 cro, lac headpiece and a mutant lac headpiece resembling the gal repressor headpiece with the recognition helices in correct and reversed orientations in the DNA major groove. The inclusion of experimental data gives an improved convergence of the correctly oriented structures and allows for an easier discrimination between correctly and incorrectly docked complexes.