Origins of netropsin binding affinity and specificity: correlations of thermodynamic and structural data.

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Abstract
We report complete thermodynamic profiles for netropsin binding to an oligomeric and to several polymeric DNA host duplexes. These data allow us to reach the following conclusions: (i) netropsin binding by deep penetration into the minor groove is overwhelmingly enthalpy driven and exhibits a very high binding affinity (K .apprxeq. 109 at 25.degree. C); (ii) deep penetration into the minor groove is required to form those drug-DNA interactions responsible for the enthalpy-driven high binding affinity of netropsin; (iii) I.cntdot.C base pairs form binding sites for netropsin that thermodynamically are equivalent to those formed by A.cntdot.T base pairs; (iv) the positive binding entropies reflect entropic contributions from molecular events other than just water spine disruption; (v) the thermodynamic binding data primarily reflect local netropsin-DNA interactions rather than long-range binding-induced conformational changes at regions distant from the binding site; (vi) the enhanced binding affinity associated with deep penetration of netropsin into the minor groove does not result from more favorable electrostatic interactions; (vii) the binding of netropsin to the central AATT core of the decamer duplex [d(GCG-AATTCGC)]2 is thermodynamically modeled best by netropsin binding to the poly[d(AT)].cntdot.[polyd(AT)] duplex rather than the poly(dA).cntdot.poly(dT) duplex. We propose correlations between our thermodynamic data and specific molecular interactions defined by NMR and x-ray structural studies on similar and identical drug-DNA complexes.