Groove Switching of Hydroxychloroquine Modulates the Efficacy of Binding and Induced Stability to DNA.

Hydroxychloroquine (HCQ) is an important drug for the treatment of rheumatoid arthritis and malaria. HCQ targets specifically to nucleic acids for its action. However, the mechanism of HCQ binding and the effect of its binding on the stability of DNA are elusive. In this study, the binding mechanism of HCQ and the effect of binding on stability of different sequences of DNA have been investigated using spectroscopic and molecular dynamics (MD) simulation techniques. HCQ binds with all of the sequences of DNA and stabilizes them. However, binding efficacy of HCQ with DNA depends on its sequences as the binding constant is highest for pure guanine-cytosine (G-C) rich DNA and decreases with the increase of adenine-thymine (A-T) bases. HCQ prefers to interact with AT DNA through the minor groove whereas the major groove along with intercalation are the favorable binding mode in the case of GC DNA. The binding of HCQ in the major groove of GC DNA enhances the stacking between the bases compared to the case of AT DNA which leads to higher stability for GC DNA. It appears that the groove switching of HCQ is correlated with binding affinity as well as stability of different sequences of DNA.