MONTY: a Monte Carlo approach to protein-DNA recognition

A Monte Carlo method is described for automated docking of proteins on DNA. The simulation program MONTY keeps the entire DNA and the protein backbone and core fixed while protein surface side-chains are allowed to rotate freely. The entire protein is rotated and translated by small random steps in order to find the best fit with the DNA. New configurations are accepted on basis of their Boltzmann probability. Protein-DNA interaction is represented by square well potentials for hydrogen bond and van der Waals interactions. The structure with the largest interaction energy encountered during the simulation is saved. The method is tested on complexes of the 434 Cro protein and its operator DNA where the protein is shifted up or down one or two base-pairs and is subsequently allowed to find back its native binding site. This protocol is performed for shifted complexes derived from the crystal structure, shifted complexes where the crystal structure DNA is replaced by standard B-DNA and shifted complexes where in addition the protein is replaced by protein from the uncomplexed crystal structure. In all three cases the six lowest energy structures correspond to complexes close to the native complex. The quality of sequence specific recognition diminishes, however, when the molecular surface complementarity between protein and DNA decreases.