A thermodynamic and structural analysis of DNA minor-groove complex formation

As part of an effort to develop a better understanding .of the structural a nd thermodynamic principles of DNA minor groove recognition, we have invest igated complexes of three diphenylfuran dications with the d(CGCGAATTCGCG)( 2) duplex. The parent compound, furamidine (DB75), has hive amidine substit uents while DB244 has cyclopentyl amidine substituents and DB226 has 3-pent yl amidines. The structure for the DB244-DNA complex is reported here and i s compared to the structure of the DB75 complex. Crystals were not obtained with DB226 but information from the DB75 and DB244 structures as well as p revious NMR results on DB226 indicate that all three compounds bind in the minor groove at the AATT site of the duplex. DB244 and DB75 penetrate to th e floor of the groove and form hydrogen bonds with T8 on one strand and T20 on the opposite strand while DB226 forms a complex with fewer interactions . Binding studies by surface plasmon resonance (SPR) yield -Delta G degrees values in the order DB244 > DB75 > DB226 that are relatively constant with temperature. The equilibrium binding constants for DB244 are 10-20 times g reater than that for DB226. Isothermal titration calorimetric (ITC) experim ents indicate that, in contrast to Delta G degrees, Delta H degrees varies considerably with temperature to yield large negative Delta Cp degrees valu es. The thermodynamic results, analyzed in terms of structures of the DNA c omplexes, provide an explanation of why DB244 binds more strongly to DNA th an DB75, while DB266 binds more weakly. All three compounds have a major co ntribution to binding from hydrophobic interactions but the hydrophobic ter m is most favorable for DB244. DB244 also has strong contributions from mol ecular interactions in its DNA complex and all of these factors combine to give it the largest -Delta G degrees for binding. Although the factors that influence the energetics of minor groove interactions are varied and compl ex, results from the literature coupled with those on the furan derivatives indicate that there are some common characteristics for minor groove recog nition by unfused heterocyclic cations that can be used in molecular design . (C) 2000 Academic Press.