Molecular recognition between oligopeptides and nucleic acids. Sequence specific binding of (4S)‐(+)‐ and (4R)‐(−)‐dihydrokikumycin B to DNA deduced form ¹H NMR, footprinting studies and thermodynamic data

The sequence specific binding of the antibiotic (4S)‐(+)‐dihydrokikumycin B and its (4R)‐(−)enantiomer, [(S)‐I and (R)‐I, respectively] to DNA were characterized by DNase I and MPE footprinting, calorimetry, UV, spectroscopy, circular dichroism, and ¹H NMR studies. Footprinting analyses showed that both enantiomers [(S)‐I and (R)‐I] bind to AT‐rich regions of DNA. ¹H NMR studies (ligand induced chemical shift changes and NOE differences) of the dihydrokikumycins with d‐[CGCAATTGCG]₂ show unambiguously that the N to C termini of the ligands are bound to 5′‐A₅T₆T₇‐3′ reading from left to right. From quantitative 1D‐NOE studies, the AH2(5)‐ligand H7 distance of complex A [(S)‐I plus decamer (which is bound more strongely)] and complex B[(R)‐I and decamer] are estimated to be 3.8 ± 0.3 Å and 4.9 ± 0.4 Å, respectively. This difference in binding properties is reflected in the thermodynamic profiles of the two enantiomeric ligands determined by a combination of spectroscopic and calorimetric techniques. The binding freee energies (ΔG°) of (S)‐I and (R)‐I to poly d(AT)·poly d(AT) at 25°C are −31.8 and −29.3 kJ mol⁻¹, respectively while the corresponding binding enthalpies (ΔH°) are −11.3 and −0.8 kJ mol⁻¹. These data permit the construction of models for the binding of the enantiomeric dihydrokikumycins to DNA and account for the more efficient binding of the natural (S) isomer to DNA.