Cooperativity and Specificity of Cys₂His₂ Zinc Finger Protein−DNA Interactions: A Molecular Dynamics Simulation Study

Abstract

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.

A Novel Specificity Protein 1 (SP1)-like Gene Regulating Protein Kinase C-1 (Pkc1)-dependent Cell Wall Integrity and Virulence Factors in Cryptococcus neoformans

“…a canonical zinc finger motif. It is not known whether this region in S. cerevisiae plays a role in DNA binding, although recent studies suggest the importance of three zinc motifs in DNA binding (42). Nevertheless, these studies demonstrate an evolutionary divergence between the cryptococcal Sp1 and the ascomycete Crz1.…”

Thermodynamic Additivity for Impacts of Base-Pair Substitutions on Association of the Egr-1 Zinc-Finger Protein with DNA

“…53,54 Another possible explanation is that 4 or more nucleotide substitutions might adversely impact domain-domain packing and weaken positive cooperativity among the three zinc fingers within an Egr-1 molecule bound to DNA. 55,56 …”

Molecular dynamics and free energy studies on the carboxypeptidases complexed with peptide/small molecular inhibitor: Mechanism for drug resistance

“…The zinc ion was assigned only van der Waals parameters and interactions between the dummy atoms and amino acid residues were then computed using the conventional electrostatic interaction term. Here, the parameters were set referring to the strategy adopted in the literature (Lee et al, 2010). The þ2e charge of the zinc ion was restored for the subsequent binding free energy analysis.…”