Nuclear receptor-DNA binding specificity: A COMBINE and Free-Wilson QSAR analysis

Specific binding of transcription factors to DNA is crucial for gene regulation. We derived models for the binding specificity of transcription factors of the nuclear receptor family to DNA using two QSAR methods: a Free-Wilson-like method and COMparative BINding Energy (COMBINE) analysis. The analysis is based on experimental data for the interaction of 20 mutant glucocorticoid receptor DNA-binding domains with 16 different response elements in a total of 320 complexes (Zilliacus, J.; Wright, A. P.; Carlstedt-Duke, J.; Nilsson, L.; Gustafsson, J. A. Proteins 1995, 21, 57-67). The predictive abilities of the models obtained by the two methods are similar. The COMBINE analysis indicates that the most important properties for determining binding specificity for this dataset are the changes upon binding of the solvation free energies of the bases that are mutated in the dataset and the electrostatic interactions of the mutated nucleotides with certain charged amino acids. Further important descriptors are the changes of solvation free energy and surface area of the side chain of the mutated residue. It is clear, however, that there are additional features important for the specificity of binding that are not included in the models, such as differences in interfacial hydration of the complexes.