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COMBINE analysis of nuclear receptor-DNA binding specifity: Comparison of two datasets

To identify the major determinants of the DNA binding specificity of nuclear transcription factors, the Comparative Binding Energy (COMBINE) analysis has been performed for two datasets. In To-mi} et al.,1 COMBINE QSAR models were derived for a set of 320 complexes of DNA and glucocorticoid receptor mutants. Here, we derive COMBINE QSAR models for a set of 32 complexes. This set differs from the larger one in two aspects. The complexes have ad-ditional mutation sites in the DNA binding domain and, instead of just activity measurements, both activity and binding affinity mea-surements are available. Models of better predictive ability were obtained with the smaller, but experimentally better characterized, dataset. The parameters important for determining binding specificity are nevertheless similar for both datasets: the electrostatic interaction energies between the mutated nucleotides and mutated residue(s) as well as some charged amino acid residues (Arg-447, Arg-470, Arg-477), and the solvation free energies of the mutated base(s). However, the relative importance of these parameters is different in the two datasets.

Quantitative Structure-Activity Relationship (QSAR); COMBINE analysis; molecular modeling; gene regulation; molecular mechanics

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