Partial intercalation with DNA of peptides containing two aromatic amino acids

Abstract

The interactions with DNA of tetrapeptide amides containing lysine at the N-terminal position and aromatic amino acids at the second and fourth positions (Ala at position three), 1-6, have been investigated by nmr, CD, and viscometric methods. Tetrapeptides with N-terminal lysine and a single aromatic amino acid, 7-10, were investigated as controls. Significant decreases in DNA viscosity occurred on addition of 7, with the aromatic group at the second position, but not with any of the other single aromatic amino acid peptides. All of the tetrapeptides with two aromatic groups caused DNA viscosity decreases which were two to three times larger than with 7. Peptides with p-nitrophenylalanine (p-NO2Phe) as the aromatic group were synthesized for nmr studies because of its simpler aromatic nmr spectrum relative to Phe. Large upfield shifts of the aromatic proton signals were obtained when the amino acid in the second position was L-p-NO2Phe, and the fourth position contained either p-NO2Phe or Phe. Such peptides also caused the largest DNA viscosity decreases on complex formation. Smaller upfield shifts of the aromatic signals were obtained when the amino acid in the second position was L-Phe or a D isomer of Phe or p-NO2Phe. With all peptides, larger upfield nmr shifts were obtained with heat-denatured, recooled DNA than with native DNA under the same conditions. As with nmr, CD results are quite different for the peptides with L and D amino acids at the second position. All of the results can be interpreted in terms of a model in which lysine interacts stereospecifically with the backbone in a DNA double helix and the aromatic group at the second position stacks strongly with the base pairs when the amino acid is an L isomer. The aromatic group at the fourth position can also interact with the base pairs, but primarily through a sideways stacking of the aromatic group with base pairs for either L or D isomers. Because of covalent constraints on the separation distance for the two aromatic groups in the tetrapeptides, they must stack on opposite sides of the same base pair in violation of the neighbor exclusion principle observed with classical intercalators. This stacking at the same base pair no doubt accounts for the larger viscosity decreases in DNA with the peptides containing two aromatic groups relative to those with a single aromatic group.(ABSTRACT TRUNCATED AT 400 WORDS)

Mutation of a Conserved Serine Residue in a Quinolone-resistant Type II Topoisomerase Alters the Enzyme-DNA and Drug Interactions

“…The data of this study are consistent with a direct interaction of the HTH motif with DNA (44). Peptides containing aromatic amino acids are known to be capable of partial intercalation with DNA (45). NMR titrations with complexes between double-strand DNA and tryptophan-containing peptides confirmed the possibility of intercalation (46).…”

Observation of daunomycin and nogalamycin complexes with duplex DNA using electrospray ionisation mass spectrometry

“…A variety of nonclassical intercalators are known to stack on opposite sides of the same base pair in violation of this principle. 34,35 Alternatively, these ions may be the result of electrostatic interactions between the positively charged amine of daunomycin and the phosphate backbone of DNA. That higher numbers of bound drug were not observed for nogalamycin is perhaps not surprising given that the binding will be more restricted than daunomycin owing to the dumbbell shape of nogalamycin requiring the DNA helix to 'breathe' to allow intercalation.…”

An intercalation inhibitor altering the target selectivity of DNA damaging agents: Synthesis of site-specific aflatoxin B 1 adducts in a p53 mutational hotspot

“…This was not the case, however, suggesting that the neighborexclusion principle is not strictly applicable. Indeed, other violations of the neighbor-exclusion principle have been reported (30,31).…”