Differences between specific and non-specific protein-DNA interactions observed by molecular dynamics simulation

Tokuhisa, Atsushi; Kono, Hidetoshi

The "zinc-finger" motif is an essential structure for proteins that bind DNA specifically. A transcription factor protein of Zif268, which consists of three zinc-finger motifs, recognizes the target sequence GCGTGGGCGT. How dose the Zif268 protein recognize the sequence? We present a quantitative analysis of the recognition mechanism of Zif268 using molecular dynamics simulations (MD). We performed MD simulations two different systems. One is the complex of Zif268 protein and target sequence DNA and another is the complex of Zif268 and non-target sequence (GCTATAAAAG) DNA. The result shows that the non-target sequence has larger structural entropy and smaller number of stable hydrogen bonds between DNA and protein than the target sequence. This difference leads to largely slide on the DNA surface of the finger 2 of Zif268 that binds non-target sequence by a foothold of ARG 40 and ARG44 residues.