jp7b04724_si_001.pdf (3.31 MB)
All-Atom MD Predicts Magnesium-Induced Hairpin in Chemically Perturbed RNA Analog of F10 Therapeutic
journal contribution
posted on 2017-07-26, 00:00 authored by Ryan L. Melvin, William H. Gmeiner, Freddie R. SalsburyGiven
their increasingly frequent usage, understanding the chemical
and structural properties which allow therapeutic nucleic acids to
promote the death of cancer cells is critical for medical advancement.
One molecule of interest is a 10-mer of FdUMP (5-fluoro-2′-deoxyuridine-5′-O-monophosphate)
also called F10. To investigate causes of structural stability, we
have computationally restored the 2′ oxygen on each ribose
sugar of the phosphodiester backbone, creating FUMP[10]. Microsecond
time-scale, all-atom, simulations of FUMP[10] in the presence of 150
mM MgCl2 predict that the strand has a 45% probability
of folding into a stable hairpin-like secondary structure. Analysis
of 16 μs of data reveals phosphate interactions as likely contributors
to the stability of this folded state. Comparison with polydT and
polyU simulations predicts that FUMP[10]’s lowest order structures
last for one to 2 orders of magnitude longer than similar nucleic
acid strands. Here we provide a brief structural and conformational
analysis of the predicted structures of FUMP[10], and suggest insights
into its stability via comparison to F10, polydT, and polyU.