Modelling repressor proteins docking to DNA

The docking of repressor proteins to DNA starting from the unbound protein and model-built DNA coordinates is modeled computationally. The approach wa s evaluated on eight repressor/DNA complexes that employed different modes for protein/DNA recognition. The global search is based on a protein-protei n docking algorithm that evaluates shape and electrostatic complementarity, which was modified to consider the importance of electrostatic features in DNA-protein recognition. Complexes were then ranked by an empirical score for the observed amino acid/nucleotide pairings (i.e,, protein-DNA pair pot entials) derived from a database of 20 protein/DNA complexes. A good predic tion had at least 65% of the correct contacts modeled. This approach was ab le to identify a good solution at rank four or better for three out of the eight complexes. Predicted complexes were filtered by a distance constraint based on experimental data defining the DNA footprint. This improved cover age to four out of eight complexes having a good model at rank four or bett er. The additional use of amino acid mutagenesis and phylogenetic data defi ning residues on the repressor resulted in between 2 and 27 models that wou ld have to be examined to find a good solution for seven of the eight test systems. This study shows that starting with unbound coordinates one can pr edict three dimensional models for protein/DNA complexes that do not involv e gross conformational changes on association. (C) 1998 Wiley-liss, Inc.