Cooperativity and specificity of Cys2His2 zinc finger protein-DNA interactions: a molecular dynamics simulation study.

Cys(2)His(2) zinc finger proteins are one of the most frequently observed DNA-binding motifs in eukaryotes. They have been widely used as a framework for designing new DNA-binding proteins. In this work, the binding affinity and conformational change of the Zif268-DNA complex were successfully reproduced with MD simulations and MM-PBSA analysis. The following new discoveries on the zinc finger protein-DNA interactions were obtained by careful energy decomposition analysis. First, a dramatic increase in the binding affinity was observed when the third zinc finger is added, indicating a cooperative nature. This cooperativity is shown to be a consequence of the small but distinctive conformational change of DNA, which enables a tight fit of the protein into the major groove of DNA. Second, specificity of the amino acid-nucleotide recognitions observed in the crystal structure is explained as originating from the ability of specific side chains and bases to take the optimal geometries for favorable interactions between polar groups. The success of the current approach implies that similar methods could be further applied to the study of protein-DNA interactions involving longer polyfingers or different linkers between fingers to provide insights for design of novel zinc finger proteins.