Cation–π/H-bond Stair Motifs at Protein–DNA Interfaces

H-bonds and cation–π interactions between nucleic acid bases and amino acid side-chains are known to occur often concomitantly at the interface between protein and double-stranded DNA. Here we define and analyze stair-shaped motifs, which simultaneously involve base stacking, H-bond and cation–π interactions. They consist of two successive bases along the DNA stack, one in cation–π interaction with an amino acid side-chain that carries a total or partial positive charge, and the other H-bonded with the same side-chain. A survey of 52 high-resolution structures of protein/DNA complexes reveals the occurrence of such motifs in the majority of the complexes, the most frequent of these motifs involving Arg side-chains and G bases. These stair motifs are sometimes part of larger motifs, called multiple stair motifs, which contain several successive stairs; zinc finger proteins for example exhibit up to quadruple stairs. In another kind of stair motif extension, termed cation–π chain motif, an amino acid side-chain or a nucleic acid base forms simultaneously two cation–π interactions. Such a motif is observed in several homeodomains, where it involves a DNA base in cation–π interactions with an Arg in the minor groove and an Asn in the major groove. A different cation–π chain motif contains an Arg in cation–π with a G and a Tyr, and is found in ets transcription factors. Still another chain motif is encountered in proteins that expulse a base from the DNA stack and replace it by an amino acid side-chain carrying a net or partial positive charge, which forms cation–π interactions with the two neighboring bases along the DNA strand. The striking conservation of typical stair and cation–π chain motifs within families of protein/DNA complexes suggests that they might play a structural and/or functional role and might moreover influence electron migration through the DNA double helix.