Setting anchor in the minor groove: in silico investigation into formamido N-methylpyrrole and N-methylimidazole polyamides bound by cognate DNA sequences.

Tricyclic N-methylpyrrole (Py) and N-methylimidazole (Im) containing polyamide monocations are known to bind as stacked dimers within the minor groove of DNA, and those with N-terminal formamido (f) substituents bind in a staggered configuration with high specificity over a range of affinities. Although binding constants have been reported, there is not a clear understanding of why such constants vary significantly for polyamide dimers and their respective cognate DNA sequences. By employing computational tools, the following homodimer complexes have been addressed in this study: f-PyPyIm in complex with 5'-d(GAACTAGTTC)-3', f-ImPyPy in complex with 5'-d(GAATGCATTC)-3', and f-ImPyIm in complex with 5'-d(GAACGCGTTC)-3'. These complexes were selected based on their 10- to 100-fold differences in binding constants. From this study, it was possible to determine how polyamides anchor themselves within the minor groove of specific DNA sequences. This is done through several interactions that provide stability for specific recognition: (i) Py groups secure themselves between DNA base pairs, (ii) lone-pair-Π interactions are formed between DNA deoxyribose O4' and Im groups nearest f, (iii) minor groove bases hydrogen bond to Im groups and amides of the polyamide backbone, (iv) f substituents rotate without leaving the minor groove of DNA and with this rotation form specific hydrogen bonds with electron-rich sites on the floor of the minor groove, and (v) flexible charged N,N-dimethylaminoalkyl substituents reside favorably in the minor groove of DNA. Results displayed the greatest amount of interactions and stability for dimer f-ImPyIm in complex with 5'-d(GAACGCGTTC)-3' and the least amount in dimer f-PyPyIm in complex with 5'-d(GAACTAGTTC)-3'. Hence, for cognate DNA sequences, the relative binding strength of compounds was determined as f-ImPyIm > f-ImPyPy > f-PyPyIm. This force-field-based computational study is in agreement with experimental results and provides a molecular rational for the binding constant values.