2 research outputs found
Effect of Monovalent Ion Parameters on Molecular Dynamics Simulations of GâQuadruplexes
G-quadruplexes (GQs)
are key noncanonical DNA and RNA architectures
stabilized by desolvated monovalent cations present in their central
channels. We analyze extended atomistic molecular dynamics simulations
(âŒ580 ÎŒs in total) of GQs with 11 monovalent cation parametrizations,
assessing GQ overall structural stability, dynamics of internal cations,
and distortions of the G-tetrad geometries. Majority of simulations
were executed with the SPC/E water model; however, test simulations
with TIP3P and OPC water models are also reported. The identity and
parametrization of ions strongly affect behavior of a tetramolecular
dÂ[GGG]<sub>4</sub> GQ, which is unstable with several ion parametrizations.
The remaining studied RNA and DNA GQs are structurally stable, though
the G-tetrad geometries are always deformed by bifurcated H-bonding
in a parametrization-specific manner. Thus, basic 10-ÎŒs-scale
simulations of fully folded GQs can be safely done with a number of
cation parametrizations. However, there are parametrization-specific
differences and basic force-field errors affecting the quantitative
description of ion-tetrad interactions, which may significantly affect
studies of the ion-binding processes and description of the GQ folding
landscape. Our dÂ[GGG]<sub>4</sub> simulations indirectly suggest that
such studies will also be sensitive to the water models. During exchanges
with bulk water, the Na<sup>+</sup> ions move inside the GQs in a
concerted manner, while larger relocations of the K<sup>+</sup> ions
are typically separated. We suggest that the Joung-Cheatham SPC/E
K<sup>+</sup> parameters represent a safe choice in simulation studies
of GQs, though variation of ion parameters can be used for specific
simulation goals
Can We Execute Reliable MM-PBSA Free Energy Computations of Relative Stabilities of Different Guanine Quadruplex Folds?
The self-assembly and stability of
DNA G-quadruplexes (GQs) are
affected by the intrinsic stability of different GpG base steps embedded
in their G-quartet stems. We have carried out MD simulations followed
by MM-PBSA (molecular mechanics PoissonâBoltzmann surface area)
free energy calculations on all the experimentally observed three-quartet
intramolecular human telomeric GQ topologies. We also studied antiparallel
GQ models with alternative <i>syn</i>-<i>anti</i> patterns of the G-quartets. We tested different ions, dihedral variants
of the DNA force field, water models, and simulation lengths. In total,
âŒ35 ÎŒs of simulations have been carried out. The systems
studied here are considerably more complete than the previously analyzed
two-quartet stems. Among other effects, our computations included
the stemâloop coupling and ionâion interactions inside
the stem. The calculations showed a broad agreement with the earlier
predictions. However, the increase in the completeness of the system
was associated with increased noise of the free energy data which
could be related, for example, to the presence of long-lived loop
substates and rather complex dynamics for the two bound ions inside
the G-stem. As a result, the MM-PBSA data were noisy and we could
not improve their quantitative convergence even by expanding the simulations
to 2.5 ÎŒs long trajectories. We also suggest that the quality
of MM-based free energy computations based on MD simulations of complete
GQs is more sensitive to the neglect of explicit polarization effects,
which, in real systems, are associated with the presence of multiple
closely spaced ions inside the GQs. Thus, although the MM-PBSA procedure
provides very useful insights that complement the structural-dynamics
data from MD trajectories of GQs, the method is far from reaching
quantitative accuracy. Our conclusions are in agreement with critical
assessments of the MM-PBSA methodology available in contemporary literature
for other types of problems