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Targeting G-quadruplex DNA and B-DNA with a natural alkaloid: a comparative spectroscopic study

Mandal, Paulami, Bhattacharya, Maitree, Chowdhury, Joydeep
RSC advances 2016 v.6 no.111 pp. 109846-109856
B-DNA, alkaloids, anisotropy, computer simulation, gene therapy, models, spectral analysis, spectroscopy, telomeres, toxicity
The present research compared the binding mechanisms of natural alkaloid harmine (HR) with two structurally different biologically important DNA species, human telomeric 22 G-quadruplex DNA (GQ-DNA) and B-DNA using various steady state and time-resolved spectroscopic techniques. Our study shows that for both DNA species HR has appreciable ground state interaction with comparable binding strengths. When HR binds, GQ-DNA which initially remained as mixed-hybrid structure converted to parallel types whereas the B-DNA structure perturbed through intercalation. HR displayed modest selectivity for the quadruplex over duplex B-DNA and binds in grooves and/or loops over external end stacking with quadruplex instead of intercalation with B-DNA. Switching of stabilization from moderate to strong occurred while HR binds with GQ-DNA and B-DNA respectively. The difference in the dynamics of HR in with both DNAs has been described well by the wobbling-in-cone model from the time-resolved anisotropy data. Our time-resolved results interpreted the dynamics of HR in both DNA environments suggesting favourable loop and/or groove binding of HR with GQ-DNA over partial end-stacking and intercalation mode of binding with B-DNA. Steady state anisotropy measurements and molecular docking further confirmed our conclusions regarding binding mechanisms. The present study could be highly useful in less toxic targeted gene therapy.