7 research outputs found
QM Computations on Complete Nucleic Acids Building Blocks: Analysis of the Sarcin–Ricin RNA Motif Using DFT-D3, HF-3c, PM6-D3H, and MM Approaches
A set of conformations obtained from
explicit solvent molecular
dynamics (MD) simulations of the Sarcin–Ricin internal loop
(SRL) RNA motif is investigated using quantum mechanical (QM, TPSS-D3/def2-TZVP
DFT-D3) and molecular mechanics (MM, AMBER parm99bsc0+χ<sub>ol3</sub> force field) methods. Solvent effects are approximated
using implicit solvent methods (COSMO for DFT-D3; GB and PB for MM).
Large-scale DFT-D3 optimizations of the full 11-nucleotide motif are
compared to MM results and reveal a higher flexibility of DFT-D3 over
the MM in the optimization procedure. Conformational energies of the
SRL motif expose significant differences in the DFT-D3 and MM energy
descriptions that explain difficulties in MD simulations of the SRL
motif. The TPSS-D3 data are in excellent agreement with results obtained
by the hybrid functionals PW6B95-D3 and M06-2X. Computationally more
efficient methods such as PM6-D3H and HF-3c show promising but partly
inconsistent results. It is demonstrated that large-scale DFT-D3 computations
on complete nucleic acids building blocks are a viable tool to complement
the picture obtained from MD simulations and can be used as benchmarks
for faster computational methods. Methodological challenges of large-scale
QM computations on nucleic acids such as missing solvent–solute
interactions and the truncation of the studied systems are discussed
Comparative Assessment of Different RNA Tetranucleotides from the DFT-D3 and Force Field Perspective
Classical force field (FF) molecular
dynamics (MD) simulations
of RNA tetranucleotides have substantial problems in reproducing conformer
populations indicated by NMR experiments. To provide more information
about the possible sources of errors, we performed quantum mechanical
(QM, TPSS-D3/def2-TZVP) and molecular mechanics (MM, AMBER parm99bsc0+χ<sub>OL3</sub>) calculations of different r(CCCC), r(GACC), and r(UUUU)
conformers obtained from explicit solvent MD simulations. Solvent
effects in the static QM and MM calculations were mimicked using implicit
solvent models (COSMO and Poisson–Boltzmann, respectively).
The comparison of QM and MM geometries and energies revealed that
the two methodologies provide qualitatively consistent results in
most of the cases. Even though we found some differences, these were
insufficient to indicate any systematic corrections of the RNA FF
terms that could improve the performance of classical MD in simulating
tetranucleotides. On the basis of these findings, we inferred that
the overpopulation of intercalated conformers in the MD simulations
of RNA tetramers, which were not observed experimentally, might be
predominantly caused by imbalanced water–solvent and water–water
interactions. Apart from the large-scale QM calculations performed
to assess the performance of the AMBER FF, a representative spectrum
of faster QM methods was tested
Role of S‑turn2 in the Structure, Dynamics, and Function of Mitochondrial Ribosomal A‑Site. A Bioinformatics and Molecular Dynamics Simulation Study
The mRNA decoding site (A-site) in
the small ribosomal subunit
controls fidelity of the translation process. Here, using molecular
dynamics simulations and bioinformatic analyses, we investigated the
structural dynamics of the human mitochondrial A-site (native and
A1490G mutant) and compared it with the dynamics of the bacterial
A-site. We detected and characterized a specific RNA backbone configuration,
S-turn2, which occurs in the human mitochondrial but not in the bacterial
A-site. Mitochondrial and bacterial A-sites show different propensities
to form S-turn2 that may be caused by different base-pairing patterns
of the flanking nucleotides. Also, the S-turn2 structural stability
observed in the simulations supports higher accuracy and lower speed
of mRNA decoding in mitochondria in comparison with bacteria. In the
mitochondrial A-site, we observed collective movement of stacked nucleotides
A1408·C1409·C1410, which may explain the known differences
in aminoglycoside antibiotic binding affinities toward the studied
A-site variants
Effect of Monovalent Ion Parameters on Molecular Dynamics Simulations of G‑Quadruplexes
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
(∼580 μs 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
d[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-μs-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 d[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
Noncanonical α/γ Backbone Conformations in RNA and the Accuracy of Their Description by the AMBER Force Field
The sugar–phosphate backbone
of RNA can exist in diverse
rotameric substates, giving RNA molecules enormous conformational
variability. The most frequent noncanonical backbone conformation
in RNA is α/γ = t/t, which is derived from the canonical
backbone by a crankshaft motion and largely preserves the standard
geometry of the RNA duplex. A similar conformation also exists in
DNA, where it has been extensively studied and shown to be involved
in DNA–protein interactions. However, the function of the α/γ
= t/t conformation in RNA is poorly understood. Here, we present molecular
dynamics simulations of several prototypical RNA structures obtained
from X-ray and NMR experiments, including canonical and mismatched
RNA duplexes, UUCG and GAGA tetraloops, Loop E, the sarcin–ricin
loop, a parallel guanine quadruplex, and a viral pseudoknot. The stability
of various noncanonical α/γ backbone conformations was
analyzed with two AMBER force fields, ff99bsc0χ<sub>OL3</sub> and ff99bsc0χ<sub>OL3</sub> with the recent εζ<sub>OL1</sub> and β<sub>OL1</sub> corrections for DNA. Although
some α/γ substates were stable with seemingly well-described
equilibria, many were unstable in our simulations. Notably, the most
frequent noncanonical conformer α/γ = t/t was unstable
in both tested force fields. Possible reasons for this instability
are discussed. Our work reveals a potentially important artifact in
RNA force fields and highlights a need for further force field refinement
Microsecond-Scale MD Simulations of HIV‑1 DIS Kissing-Loop Complexes Predict Bulged-In Conformation of the Bulged Bases and Reveal Interesting Differences between Available Variants of the AMBER RNA Force Fields
We report an extensive set of explicit
solvent molecular dynamics
(MD) simulations (∼25 μs of accumulated simulation time)
of the RNA kissing-loop complex of the HIV-1 virus initiation dimerization
site. Despite many structural investigations by X-ray, NMR, and MD
techniques, the position of the bulged purines of the kissing complex
has not been unambiguously resolved. The X-ray structures consistently
show bulged-out positions of the unpaired bases, while several NMR
studies show bulged-in conformations. The NMR studies are, however,
mutually inconsistent regarding the exact orientations of the bases.
The earlier simulation studies predicted the bulged-out conformation;
however, this finding could have been biased by the short simulation
time scales. Our microsecond-long simulations reveal that all unpaired
bases of the kissing-loop complex stay preferably in the interior
of the kissing-loop complex. The MD results are discussed in the context
of the available experimental data and we suggest that both conformations
are biochemically relevant. We also show that MD provides a quite
satisfactory description of this RNA system, contrasting recent reports
of unsatisfactory performance of the RNA force fields for smaller
systems such as tetranucleotides and tetraloops. We explain this by
the fact that the kissing complex is primarily stabilized by an extensive
network of Watson–Crick interactions which are rather well
described by the force fields. We tested several different sets of
water/ion parameters but they all lead to consistent results. However,
we demonstrate that a recently suggested modification of van der Waals
interactions of the Cornell et al. force field deteriorates the description
of the kissing complex by the loss of key stacking interactions stabilizing
the interhelical junction and excessive hydrogen-bonding interactions
Microsecond-Scale MD Simulations of HIV‑1 DIS Kissing-Loop Complexes Predict Bulged-In Conformation of the Bulged Bases and Reveal Interesting Differences between Available Variants of the AMBER RNA Force Fields
We report an extensive set of explicit
solvent molecular dynamics
(MD) simulations (∼25 μs of accumulated simulation time)
of the RNA kissing-loop complex of the HIV-1 virus initiation dimerization
site. Despite many structural investigations by X-ray, NMR, and MD
techniques, the position of the bulged purines of the kissing complex
has not been unambiguously resolved. The X-ray structures consistently
show bulged-out positions of the unpaired bases, while several NMR
studies show bulged-in conformations. The NMR studies are, however,
mutually inconsistent regarding the exact orientations of the bases.
The earlier simulation studies predicted the bulged-out conformation;
however, this finding could have been biased by the short simulation
time scales. Our microsecond-long simulations reveal that all unpaired
bases of the kissing-loop complex stay preferably in the interior
of the kissing-loop complex. The MD results are discussed in the context
of the available experimental data and we suggest that both conformations
are biochemically relevant. We also show that MD provides a quite
satisfactory description of this RNA system, contrasting recent reports
of unsatisfactory performance of the RNA force fields for smaller
systems such as tetranucleotides and tetraloops. We explain this by
the fact that the kissing complex is primarily stabilized by an extensive
network of Watson–Crick interactions which are rather well
described by the force fields. We tested several different sets of
water/ion parameters but they all lead to consistent results. However,
we demonstrate that a recently suggested modification of van der Waals
interactions of the Cornell et al. force field deteriorates the description
of the kissing complex by the loss of key stacking interactions stabilizing
the interhelical junction and excessive hydrogen-bonding interactions