SEQUENCE-SELECTIVE DNA-BINDING BY LINKED BIS-N-METHYLPYRROLE DIPEPTIDES - AN ANALYSIS BY MPE FOOTPRINTING AND FORCE-FIELD CALCULATIONS

The binding of a series of linked bis-oligopeptides, designed to examine the phasing problem of the molecular recognition by longer ligands of DNA sequences, was examined by MPE complementary strand footprinting on a EcoRI/HindIII restriction fragment of pBR322 DNA. Ligands bearing N-methylpyrrole dipeptide moieities linked by trans olefinic or trans 1,2-cycloalkane moieties (n = 3, 4, 5, 6) give evidence of bidentate binding in (AT)(n) rich sequences from footprinting at r' = 0.16. By contrast those ligands linked by cis olefinic or cis 1,2-cyclopropane tethers exhibit monodentate binding. These results on the relative binding of cis and trans isomeric ligands are corroborated by detailed studies employing ultraviolet and circular dichroism spectroscopic studies on representative pairs of compounds which permit, inter alia, the determination of binding parameters, stoichiometry, and association constants. Consideration of the energetics of binding of cis-trans pairs of ligands suggests operational rather than true bidentate binding of the trans compounds via a ''dancing'' mode. The influence of ligand conformation and other structural parameters on the efficiency of drug binding was examined by a detailed force field analysis employing the MMX program. These calculations permitted the interpretation of the experimental data and comparison with ''ideal'' minor groove binders.