Pyrrole-imidazole polyamides distinguish between double-helical DNA and RNA

Abstract

Groove specificity: pyrrole-imidazole polyamides are well-known for their specific interactions with the minor groove of DNA. However, polyamides do not show similar binding to duplex RNA, and a structural rationale for the molecular-level discrimination of nucleic acid duplexes by minor-groove-binding ligands is presented.

Figure 1

Structures of polyamides 1–3 and their DNA binding sites. Polyamide shorthand code: closed circles, N-methylimidazole; open circles, N-methylpyrrole; half diamond with cross, 3,3’-diamino-N-methyl-dipropylamine; Dp, 3-(dimethylamino)-propylamine; IPA, isophthalic acid.

Figure 2

Comparison of the overall structure of dsDNA in the presence and absence of polyamide to the analogous sequence of dsRNA. a) X-ray structure (PDB: 3OMJ) of polyamide 3 complexed to the DNA sequence d(5'-CCAGTACTGG-3') solved at 0.95 Å.^[16] Electron density map of the polyamide is contoured at the 1.0 σ level. b) Native DNA structure (PDB: 1D8G) d(5'-CCAGTACTGG-3') solved at ultrahigh resolution (0.74 Å) by Rees and coworkers.^[21] c) Model of ideal A-form dsRNA for comparison.

Figure 3

Structural basis for selective dsDNA versus dsRNA binding. a) Crystal structure of DNA-polyamide 3 complex (PDB: 3OMJ) showing shape complementary and favorable hydrophobic interactions with the sugar-phosphate backbone (gray). Orange, polyamide; blue, aromatic DNA bases. b) Coordinates of cyclic polyamide 3 docked in the minor groove of the putative binding site on a model of ideal A-form dsRNA.