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All-atom MD indicates ion-dependent behavior of therapeutic DNA polymer

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Abstract

Understanding the efficacy of and creating delivery mechanisms for therapeutic nucleic acids requires understanding structural and kinetic properties which allow these polymers to promote the death of cancerous cells. One molecule of interest is a 10 mer of FdUMP (5-fluoro-2′-deoxyuridine-5′-O-monophosphate) – also called F10. Here we investigate the structural and kinetic behavior of F10 in intracellular and extracellular solvent conditions along with non-biological conditions that may be efficacious in in vitro preparations of F10 delivery systems. From our all-atom molecular dynamics simulations totaling 80 microseconds, we predict that F10's phosphate groups form close-range interactions with calcium and zinc ions, with calcium having the highest affinity of the five ions investigated. We also predict that F10's interactions with magnesium, potassium and sodium are almost exclusively long-range interactions. In terms of intramolecular interactions, we find that F10 is least structured (in terms of hydrogen bonds among bases) in the 150 mM NaCl (extracellular-like solvent conditions) and most structured in 150 mM ZnCl2. Kinetically, we see that F10 is unstable in the presence of magnesium, sodium or potassium, finding stable kinetic traps in the presence of calcium or zinc.

Graphical abstract: All-atom MD indicates ion-dependent behavior of therapeutic DNA polymer

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Publication details

The article was received on 23 May 2017, accepted on 04 Aug 2017 and first published on 07 Aug 2017


Article type: Paper
DOI: 10.1039/C7CP03479B
Citation: Phys. Chem. Chem. Phys., 2017, Advance Article
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    All-atom MD indicates ion-dependent behavior of therapeutic DNA polymer

    R. L. Melvin, W. H. Gmeiner and F. R. Salsbury, Phys. Chem. Chem. Phys., 2017, Advance Article , DOI: 10.1039/C7CP03479B

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