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The interactions of actinomycin D with DNA serve as a paradigm for DNA base sequence selectivity through its demonstrated preference for binding to the d(GpC) step. Using the photoreactive 7-azido-actinomycin D, we have demonstrated that actinomycin D binding to DNA is more promiscuous than previously reported, with additional strong binding to ‘atypical’ sequences such as d(GpG) and d(GpGpG) steps. Similarly, our laboratory has demonstrated that the 5′-flanking base adjacent to the d(GpC) intercalation site plays a significant role in directing the thermodynamic mechanism associated with complex formation. Isothermal titration calorimetry (ITC) and UV–visible spectroscopy have been used to discern thermodynamic and kinetic properties associated with complex formation. These studies reveal significant thermodynamic and kinetic changes resulting from single-base modification to the 5′-flanking base. Historically, the interactions of actinomycin with native DNAs have been characterized as an entropy-driven process with observed binding enthalpies of approximately 0 to −1 kcal mol−1. The interaction of actinomycin D with the -TGCA- duplex is characterized by a high binding affinity and large favourable binding entropy. However, substitution of the 5′-T to 5′-C results in complex formation that is characterised by a large favourable binding enthalpy (−7 kcal mol−1). Hence, subtle changes to the DNA intercalation sequence or bases adjacent to the intercalation step results in significant changes in the thermodynamic binding mechanism for the ligand.

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