Minor groove orientation of the KWKK peptide tethered via the N-terminal amine to the acrolein-derived 1, N ²-γ- hydroxypropanodeoxyguanosine lesion with a trimethylene linkage

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′ (X = N²-dG-trimethylene link-KWKK). This linkage is a surrogate for the reversible linkage formed by the γ-OH-1,N²-propanodeoxyguanosine (γ-OH-PdG) adduct. This conjugated KWKK stabilizes the DNA. Amino acids K²⁶, W²⁷, K²⁸, and K²⁹ are in the minor groove. The W²⁷ indolyl group does not intercalate into the DNA. The G⁷ N² amine and the K²⁶ N-terminal amine nitrogens are in the trans configuration with respect to the C_α or C_γ of the trimethylene tether, respectively. The structure of this DNA-KWKK conjugate is discussed in the context of its biological processing.