Abstract
In naked duplex DNA, G–C and A–T Watson-Crick base pairs exist in dynamic equilibrium with their Hoogsteen counterparts. Here, we used nuclear magnetic resonance (NMR) relaxation dispersion and molecular dynamics (MD) simulations to examine how Watson-Crick/Hoogsteen dynamics are modulated upon recognition of duplex DNA by the bisintercalator echinomycin and monointercalator actinomycin D. In both cases, DNA recognition results in the quenching of Hoogsteen dynamics at base pairs involved in intermolecular base-specific hydrogen bonds. In the case of echinomycin, the Hoogsteen population increased 10-fold for base pairs flanking the chromophore most likely due to intermolecular stacking interactions, whereas actinomycin D minimally affected Hoogsteen dynamics at other sites. Modulation of Hoogsteen dynamics at binding interfaces may be a general phenomenon with important implications for DNA–ligand and DNA–protein recognition.
Highlights
In naked duplex DNA, G–C and A–T Watson-Crick base pairs exist in dynamic equilibrium with their Hoogsteen counterparts
Recent nuclear magnetic resonance (NMR) studies have started to challenge this paradigm by showing that in naked canonical duplex DNA, G–C and A–T Watson-Crick bps exist in a dynamic equilibrium with short-lived low-abundance Hoogsteen bps[1,2] (Fig. 1)
As a first step toward examining whether or not Hoogsteen breathing is modulated on DNA recognition, we used NMR in concert with molecular dynamics (MD) simulations to characterize changes in WatsonCrick/Hoogsteen breathing that follows recognition by two different small molecules; echinomycin and actinomycin D
Summary
In naked duplex DNA, G–C and A–T Watson-Crick base pairs exist in dynamic equilibrium with their Hoogsteen counterparts. We used nuclear magnetic resonance (NMR) relaxation dispersion and molecular dynamics (MD) simulations to examine how WatsonCrick/Hoogsteen dynamics are modulated upon recognition of duplex DNA by the bisintercalator echinomycin and monointercalator actinomycin D. In both cases, DNA recognition results in the quenching of Hoogsteen dynamics at base pairs involved in intermolecular base-specific hydrogen bonds. Changes in Hoogsteen dynamics on recognition of DNA by proteins or small molecules could potentially be widespread and play important roles determining the binding affinity and specificity, rates of complex formation, as well as downstream biological activity. Our results expose a new layer of structural plasticity at the interfaces
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