Stacking-unstacking of the dinucleoside monophosphate guanylyl-3',5'-uridine studied with molecular dynamics

Abstract

Molecular dynamics simulations were carried out on two conformations of the dinucleoside monophosphate guanylyl-3',5'-uridine (GpU) in aqueous solution with one sodium counterion. One stacked conformation and one with the C3'-O3'-P-O5' backbone torsion angle twisted 180 degrees to create an unstacked conformation. We observed a relatively stable behavior of the stacked conformation, which remained stacked throughout the simulation, whereas the unstacked conformation showed major changes in the backbone torsion and glycosidic angles. During the simulation the unstacked conformation transformed into a more stacked form and then back again to an unstacked one. The calculated correlation times for rotational diffusion from the molecular dynamics simulations are in agreement with fluorescence anisotropy and nuclear magnetic resonance data. As expected, the correlation times for rotational diffusion of the unstacked conformation were observed to be longer than for the stacked conformation. The 2'OH group may contribute in stabilizing the stacked conformation, where the O2'-H...O4' hydrogen bond occurred in 82.7% of the simulation.

Stacking Free Energies of All DNA and RNA Nucleoside Pairs and Dinucleoside-Monophosphates Computed Using Recently Revised AMBER Parameters and Compared with Experiment

“…That said, it remains interesting that our values compare somewhat better than the two sets of computed values reported previously; it is to be noted that we did not adjust our criteria for defining stacking in order to optimize agreement with experiment (see Methods). In one respect this result is encouraging, but in another it is simply to be expected: force fields in general have developed considerably in the years since the Nilsson group’s seminal studies 12–16 were performed and a number of important updates 20a, 20e, 23 have since been made to the AMBER force field used in the Florian group’s studies. 19 Differences between our data and the Florian group’s data may also be at least partly due to the different temperatures at which the studies were conducted (298 versus 310 K respectively): the Nilsson group has previously shown that stacking PMFs can be sensitive to temperature, 15 an issue that has also been examined in detail by Chen & Garcia (see below).…”

“…11 The thermodynamics of intramolecular stacking interactions, such as those found in DNMPs, have also been studied computationally by a number of groups using explicit-solvent molecular dynamics (MD) methods. Comprehensive studies of the DNMPs were pioneered by the Nilsson group 12 who computed the thermodynamics of stacking in all 16 possible DNMPs for both DNA 13 and RNA 14 by computing potentials of mean force (PMFs) with umbrella sampling techniques; later work by the same group carried out simulations over a range of temperatures to compute enthalpies of stacking 15 and examined the effects of solvents, other than water, on stacking thermodynamics. 16 The Okamoto group reported similar PMF calculations 17 for all 16 DNA DNMPs using replica exchange techniques in combination with umbrella sampling; quite different results were obtained from those reported by the Nilsson group but these differences were suggested to be most likely due to the use of different parameter sets (force fields) in the simulations.…”

Additive CHARMM force field for naturally occurring modified ribonucleotides

“…Methylation effects on dinucleotides have been reported in several NMR studies, and analysis of base stacking using dinucleotides was also previously performed using simulations, primarily using umbrella sampling . In MD simulations of 100 ns we found that the dinucleotides were less ordered due to thermal motion, so the effects of the modification were not evident (data not shown).…”

Dynamic Water Networks in Cytochrome c Oxidase from Paracoccus denitrificans Investigated by Molecular Dynamics Simulations

“…For the 88 water molecules found in the crystal structure plus the 176 water molecules from the GRID calculations (W12 set of coordinates), D H2O was (3.0 6 0.005) 3 10 -9 m 2 /s, and for the 88 structural water molecules plus the 755 water molecules from the W8 set of coordinates, D H2O was (3.1 6 0.005) 3 10 -9 m 2 /s. Experimental values for D H2O at 300 K are 2.3 3 10 -9 m 2 / s (Mills, 1973), and in pure TIP3P water (Jorgensen et al, 1983) at 300 K D H2O has been estimated to be 1.3-4.2 3 10 -9 m 2 /s (Norberg and Nilsson, 1994). The simulations show interesting features concerning the water distribution around the hemes.…”