For many years now, isothermal titration calorimetry (ITC) has been regarded as the �gold standard� approach for the characterization of biomolecular interactions.  In the current work, ITC was used to study the relative DNA binding affinity and preferred DNA mode adopted by a series of naphthalene diimides (NDI) with N-methyl pyrrolidine or N-methyl piperidine groups at distal ends of their side chain. The effect of ring size and linker length was investigated. The approach was based on the ability of ITC to detect the relative DNA binding ability of the compounds to calf thymus (ct) DNA, as well as to AT vs. GC-rich 20-mer DNA sequences. The inclusion of a cyclic component in the NDI side chain resulted in biphasic raw calorimetric data when binding to ct-DNA. The raw data were best defined by a two-site model and argues for the involvement of at least two different types of binding sites. A derivative with N-methyl piperidine substituents (K1=1.70 �0.4 x 107 M-1 and K2=3.26 �0.54 x 106 M-1) showed strong but lower ct-DNA affinity as compared to the N-methyl pyrrolidine derivatives (K1 = 1.17� 0.3 x 108 M-1, K2 = 5.6�0.65 x 106 M-1). Given the difference in size, this argues for contributions from steric bulk.  Derivatives possessing an ethylamino linker exhibited a roughly two-fold preference for the AT-rich DNA relative to the GC-rich sequence, while a derivative with a propylamino linker showed no significant preference, implying an additional binding mode for derivatives with an ethylamino linker. However, the small difference in linker length did not appear to play a significant role in the ct-DNA binding affinity.  It therefore appears that the size of the cyclic substituent plays a greater role than the linker length in determining DNA binding affinity.

Using isothermal titration calorimetry (ITC) to study the DNA binding efficacy of naphthalene diimides with <i>N</i>-methyl pyrrolidine and -piperidine substituents

247th National Meeting (2014)

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Using isothermal titration calorimetry (ITC) to study the DNA binding efficacy of naphthalene diimides with N-methyl pyrrolidine and -piperidine substituents