Minor Groove Orientation of the KWKK Peptide Tethered via the N-Terminal Amine to the Acrolein-Derived 1,N-2-gamma-Hydroxypropanodeoxyguanosine Lesion with a Trimethylene Linkage

摘要

DNA protein conjugates are potentially repaired via proteolytic digestion to DNA peptide conjugates. The latter have been modeled with the amino-terminal lysine of the peptide KWKK conjugated via a trimethylene linkage to the N-2-dG amine positioned in 5'-d(GCTAGCXAGTCC)-3'. 5'-d(GGACTCGCTAGC)-3' = N-2-dG trimcthylene link KWKK). This linkage is a surrogate for the reversible linkage formed by the gamma-OH-1,N-2-joropanodeoxyguanosine (gamma-OH-PdG) adduct. This conjugated KWKK stabilizes the DNA. Amino acids K-26, W-27, K-28, and K-29 are in the minor groove. The W-27 indolyl group does not intercalate into the DNA. The G(7) N-2 amine and the K-26 N-terminal amine nitrogens are in the trans configuration with respect to the C-alpha or C-gamma of the trimethylene tether, respectively. The structure of this DNA KWKK conjugate is discussed in the context of its biological processing.