A Theoretical Study of the Nonintercalative Binding of Berenil and Stilbamidine to Double-stranded (dA-dT)n Oligomers

The nonintercalative binding of two diarylamidines , berenil and stilbamidine , to the minor groove of double-stranded (dA-dT)n oligomers in the B-DNA conformation was investigated by performing theoretical computations of their intermolecular interaction energies with the groove. The method consists of an additive procedure developed previously in this laboratory using empirical formulae based on ab initio computations. The objective was to assess the extent to which the particular structure of each diarylamidine bears on its binding mode and affinity to the minor groove. The results show that the intrinsically preferred configurations of the two compounds are markedly different. Owing to its slightly curved shape, berenil interacts with the groove predominantly through its concave side, the binding occurring principally with sites (O2, O1) belonging to two thymidines on the opposite strands. The binding of stilbamidine involves a more limited number of hydrogen-bonding interactions, although an appreciably large number of interatomic distances between its hydrogens and sites on the groove (O2, N3, O1) falls in the range 2.7-3.1 A. Each side of stilbamidine with respect to its long axis faces a distinct strand of DNA. The importance of the electrostatic contribution of the binding energy of the two diarylamidines is underlined. Preferential binding of berenil rather than of stilbamidine occurs only at the level of a complete helical turn of phosphates in (dA-dT)n. The energy difference increases significantly upon further buildup of phosphates. These results can be interpreted in terms of the molecular electrostatic potential in the grooves.