All-Atom MD Predicts Magnesium-Induced Hairpin in Chemically Perturbed RNA Analog of F10 Therapeutic

Abstract

Given 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.

Quality Threshold Clustering of Molecular Dynamics: A Word of Caution

“…On a careful analysis of 31 scientific works (Supporting Information, Scheme S1) claiming to use QT to retrieve clusters from MD trajectories, we identify two common pitfalls (labeled as P1 and P2) that appear in the current literature. In the first group of works (P1), − the authors explicitly describe the algorithm they were using as if it were QT, citing the original paper of Heyer et al Only two of them correctly described the algorithm as Daura’s clustering but still cited the incorrect reference, Heyer et al In the second group of works (P2), − the authors do not thoroughly describe the algorithm used but do affirm performing QT when actually they performed Daura’s clustering.…”

Allosteric Modulation of Thrombin by Thrombomodulin: Insights from Logistic Regression and Statistical Analysis of Molecular Dynamics Simulations

“…55 This matrix indicates how pairs of residues move in relation to each other, a critical aspect in understanding allosteric communication pathways in proteins and protein complexes. 22,23,26,[31][32][33][34][36][37][38]55 i j…”

“…These simulations were executed using the GPU-accelerated ACEMD3 simulation package on NVIDIA Titan GPUs housed within Metrocubo workstations. The simulation protocols described below are standard with ACEMD and have been successfully used in previous works on thrombin and other systems. − ,− …”

“…The use of GPU-enabled simulations conferred a significant advantage, enabling us to extend each simulation to 50 times the duration of prior computational studies on TM456 . We have used such simulations before to study the dynamic allostery of thrombin due to ion binding, mutation, and aptamer binding as well as to study dynamic allostery in other biomedically relevant protein complexes. − …”

Using correlated motions to determine sufficient sampling times for molecular dynamics

“…In the case of a relatively unstructured [40] nucleic acid strand in two physiological solvation conditions, we see growth into the equal-time correlation on a time scale of nanoseconds [Figs. 2(a), 2(b), 4(a), 4(b), 5(a), 5(b), 6(a), and 6(b) of the Supplemental Material] indicating this would be a system in which many short simulations would be appropriate.…”