Free Energy Calculations on DNA Ligand Complexes

Ligands that interact physically with DNA have been extensively studied both by experimental techniques and by a variety of theoretical approaches. A diverse set of compounds have been studied, including compounds that intercalate between DNA sequences or bind in the minor groove.1 7 These studies have identified various factors that influence the stability of DNA ligand complexes in solution.6 8 9 

Some of the best characterized ligands that bind in the minor groove of DNA are distamycin and netropsin. Both these molecules are long and flat and are sterically and electrostatically complementary to the characteristics of the minor groove of DNA. Distamycin and netropsin are known to have specific affinity towards the minor groove of AT rich regions of B-DNA. 

The electrostatic potential calculations have shown that the minor groove of AT rich B-DNA sequence has the lowest negative potential.15 This led to the implication that the cationic drugs will exhibit binding specificity to the minor groove regions of AT rich sequences. The crystal structure of a DNA distamycin complex showed that there is only one molecule bound to the minor groove of an AATT DNA site.2 However, experimental studies 

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