Modelling repressor proteins docking to DNA

Abstract

The docking of repressor proteins to DNA starting from the unbound protein and model-built DNA coordinates is modeled computationally. The approach was evaluated on eight repressor/DNA complexes that employed different modes for protein/ DNA recognition. The global search is based on a protein-protein 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 potentials) derived from a database of 20 protein/ DNA complexes. A good prediction had at least 65% of the correct contacts modeled. This approach was able 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 coverage to four out of eight complexes having a good model at rank four or better. The additional use of amino acid mutagenesis and phylogenetic data defining residues on the repressor resulted in between 2 and 27 models that would 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 predict three-dimensional models for protein/DNA complexes that do not involve gross conformational changes on association.

AIF and cyclophilin A cooperate in apoptosis-associated chromatinolysis

“…The theoretical model of human AIF (Ye et al, 2002) was built using comparative modeling techniques as previously described . Protein-protein docking was accomplished employing 3D_Dock (Aloy et al, 1998). An angular deviation of 91 and electrostatic filtering for the total space sampling were applied.…”

“…The resulting complexes were sorted according to surface complementarity and electrostatic score values. An empirical scoring of the complexes, using residue level pair potentials (Aloy et al, 1998), was also performed. The protein interfaces obtained were then optimized using the Multidock program (Jackson et al, 1998).…”

Modelling Protein–Protein and Protein–DNA Docking

“…The approach employs the ®rst three stages of the protein-protein docking strategy amended to tackle protein±DNA complexes [34]. The steps are:…”

“…Nevertheless, there are some systems that often have only limited conformation change and to evaluate the eectiveness of predictive docking on these targets we have modelled transcriptional repressors recognising DNA [34]. The objective was to explore all possible association modes of the macromolecules.…”

“…The complexes modelled with the Protein Data Bank codes of the bound and unbound components are: ARC (arc repressor, 1par,1arr) CRO (cro repressor, 3cro, 2cro); GAL (CD2-GAL4 DNA binding domain, 1d66, 125d); LAC (lactose repressor,1lbg,1lqc); LAM (lamda phage operator repressor; 1lmb, 1lrp); MET (met repressor, 1cma, 1cmc); PUR (purR repressor, 1pnr, 1pru); TRP (trp repressor, 1tro, 2wrp). For coordinate details see Aloy et al[34]. Filter 1 employs knowledge of the central two base pairs.…”