54 research outputs found
Insight into G-DNA Structural Polymorphism and Folding from Sequence and Loop Connectivity through Free Energy Analysis
Quantum Chemical Studies of Nucleic Acids: Can We Construct a Bridge to the RNA Structural Biology and Bioinformatics Communities?
Formamide-Based Prebiotic Synthesis of Nucleobases: A Kinetically Accessible Reaction Route
Synthesis of nucleobases in nonaqueous environments is an alternative way for the emergence of terrestrial life, which could solve the fundamental problem connected to the hydrolytic instability of nucleic acid components in an aqueous environment. In this contribution, we present a plausible reaction route for the prebiotic synthesis of nucleobases in formamide, which does not require participation of the formamide trimer and aminoimidazole-carbonitrile intermediates. The computed activation energy of the proposed pathway is noticeably higher than that of the HCN-based synthetic route, but it is still feasible under the experimental conditions of the Saladino synthesis. We show that, albeit both the pyrimidine and purine ring formation utilizes the undissociated form of formamide, the dehydration product of formamide, HCN, may also play a key role in the mechanism. The rate determining step of the entire reaction path is the cyclization of the diaza-pentanimine precursor. The subsequent formation of the imidazole ring proceeds with a moderate activation energy. Our calculations thus demonstrate that the experimentally suggested reaction path without the involvement of aminoimidazole-carbonitrile intermediates is also a viable alternative for the nonaqueous synthesis of nucleobases
Comment on “Computational Model for Predicting Experimental RNA and DNA Nearest-Neighbor Free Energy Rankings”
Comment on “Computational
Model for Predicting
Experimental RNA and DNA Nearest-Neighbor Free Energy Rankings
Derivation of Reliable Geometries in QM Calculations of DNA Structures: Explicit Solvent QM/MM and Restrained Implicit Solvent QM Optimizations of G‑Quadruplexes
Modern
dispersion-corrected DFT methods have made it possible to
perform reliable QM studies on complete nucleic acid (NA) building
blocks having hundreds of atoms. Such calculations, although still
limited to investigations of potential energy surfaces, enhance the
portfolio of computational methods applicable to NAs and offer considerably
more accurate intrinsic descriptions of NAs than standard MM. However,
in practice such calculations are hampered by the use of implicit
solvent environments and truncation of the systems. Conventional QM
optimizations are spoiled by spurious intramolecular interactions
and severe structural deformations. Here we compare two approaches
designed to suppress such artifacts: partially restrained continuum
solvent QM and explicit solvent QM/MM optimizations. We report geometry
relaxations of a set of diverse double-quartet guanine quadruplex
(GQ) DNA stems. Both methods provide neat structures without major
artifacts. However, each one also has distinct weaknesses. In restrained
optimizations, all errors in the target geometries (i.e., low-resolution
X-ray and NMR structures) are transferred to the optimized geometries.
In QM/MM, the initial solvent configuration causes some heterogeneity
in the geometries. Nevertheless, both approaches represent a decisive
step forward compared to conventional optimizations. We refine earlier
computations that revealed sizable differences in the relative energies
of GQ stems computed with AMBER MM and QM. We also explore the dependence
of the QM/MM results on the applied computational protocol
Electron-Driven Proton Transfer Along H<sub>2</sub>O Wires Enables Photorelaxation of πσ* States in Chromophore–Water Clusters
The fates of photochemically formed
πσ* states are
one of the central issues in photobiology due to their significant
contribution to the photostability of biological matter, formation
of hydrated electrons, and the phenomenon of photoacidity. Nevertheless,
our understanding of the underlying molecular mechanisms in aqueous
solution is still incomplete. In this paper, we report on the results
of nonadiabatic photodynamics simulations of microhydrated 2-aminooxazole
molecule employing algebraic diagrammatic construction to the second
order. Our results indicate that electron-driven proton transfer along
H<sub>2</sub>O wires induces the formation of πσ*/S<sub>0</sub> state crossing and provides an effective deactivation channel.
Because we recently have identified a similar channel for 4-aminoimidazole-5-carbonitrile
[Szabla, R.; Phys. Chem.
Chem. Phys. 2014, 16, 17617−17626], we conclude
this mechanism may be quite common to all heterocyclic compounds with
low-lying πσ* states
Insight into G-DNA Structural Polymorphism and Folding from Sequence and Loop Connectivity through Free Energy Analysis
The lengths of G-tracts and their connecting loop sequences determine G-quadruplex folding and stability. Complete understanding of the sequence–structure relationships remains elusive. Here, single-loop G-quadruplexes were investigated using explicit solvent molecular dynamics (MD) simulations to characterize the effect of loop length, loop sequence, and G-tract length on the folding topologies and stability of G-quadruplexes. Eight loop types, including different variants of lateral, diagonal, and propeller loops, and six different loop sequences [d0 (i.e., no intervening residues in the loop), dT, dT<sub>2</sub>, dT<sub>3</sub>, dTTA, and dT<sub>4</sub>] were considered through MD simulation and free energy analysis. In most cases the free energetic estimates agree well with the experimental observations. The work also provides new insight into G-quadruplex folding and stability. This includes reporting the observed instability of the left propeller loop, which extends the rules for G-quadruplex folding. We also suggest a plausible explanation why human telomere sequences predominantly form hybrid-I and hybrid-II type structures in K<sup>+</sup> solution. Overall, our calculation results indicate that short loops generally are less stable than longer loops, and we hypothesize that the extreme stability of sequences with very short loops could possibly derive from the formation of parallel multimers. The results suggest that free energy differences, estimated from MD and free energy analysis with current force fields and simulation protocols, are able to complement experiment and to help dissect and explain loop sequence, loop length, and G-tract length and orientation influences on G-quadruplex structure
MD and QM/MM Study of the Quaternary HutP Homohexamer Complex with mRNA, l‑Histidine Ligand, and Mg<sup>2+</sup>
The HutP protein from <i>B.
subtilis</i> regulates histidine
metabolism by interacting with an antiterminator mRNA hairpin in response
to the binding of l-histidine and Mg<sup>2+</sup>. We studied
the functional ligand-bound HutP hexamer complexed with two mRNAs
using all-atom microsecond-scale explicit-solvent MD simulations performed
with the Amber force fields. The experimentally observed protein-RNA
interface exhibited good structural stability in the simulations with
the exception of some fluctuations in an unusual adenine-threonine
interaction involving two closely spaced H-bonds. We further investigated
this interaction by comparing QM/MM and MM optimizations, using the
QM region comprising almost 350 atoms described at the DFT-D3 level.
The QM/MM method clearly improved the adenine-threonine interaction
compared to MM, especially when the X–H bond lengths were frozen
during the MM optimization to mimic the use of SHAKE in the MD simulations.
Thus, both the MM approximation and the use of SHAKE can compromise
the description of H-bonds at protein-RNA interfaces. The simulations
also revealed a notable Mg<sup>2+</sup>-parameter dependence in the
behavior of the ligand-binding pocket (LBP). With the SPC/E water
model, the 12–6 Åqvist and Li&Merz parameters provided
an entirely stable LBP structure, but the 12–6 Allnér
and 12–6–4 Li&Merz parametrizations resulted in
a progressive loss of direct nitrogen–Mg<sup>2+</sup> LBP coordination.
The Allnér and Li&Merz 12–6 parametrizations were
also tested with the TIP3P water model; the LBP was destabilized in
both cases. This illustrates the difficulty of consistently describing
different Mg<sup>2+</sup> interactions using nonpolarizable force
fields. Overall, the simulations support the hypothesis that HutP
protein becomes fully structured upon ligand binding. Subsequent RNA
binding does not affect the protein structure, in keeping with the
mechanism inferred from experimental structures
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
MD and QM/MM Study of the Quaternary HutP Homohexamer Complex with mRNA, l‑Histidine Ligand, and Mg<sup>2+</sup>
The HutP protein from <i>B.
subtilis</i> regulates histidine
metabolism by interacting with an antiterminator mRNA hairpin in response
to the binding of l-histidine and Mg<sup>2+</sup>. We studied
the functional ligand-bound HutP hexamer complexed with two mRNAs
using all-atom microsecond-scale explicit-solvent MD simulations performed
with the Amber force fields. The experimentally observed protein-RNA
interface exhibited good structural stability in the simulations with
the exception of some fluctuations in an unusual adenine-threonine
interaction involving two closely spaced H-bonds. We further investigated
this interaction by comparing QM/MM and MM optimizations, using the
QM region comprising almost 350 atoms described at the DFT-D3 level.
The QM/MM method clearly improved the adenine-threonine interaction
compared to MM, especially when the X–H bond lengths were frozen
during the MM optimization to mimic the use of SHAKE in the MD simulations.
Thus, both the MM approximation and the use of SHAKE can compromise
the description of H-bonds at protein-RNA interfaces. The simulations
also revealed a notable Mg<sup>2+</sup>-parameter dependence in the
behavior of the ligand-binding pocket (LBP). With the SPC/E water
model, the 12–6 Åqvist and Li&Merz parameters provided
an entirely stable LBP structure, but the 12–6 Allnér
and 12–6–4 Li&Merz parametrizations resulted in
a progressive loss of direct nitrogen–Mg<sup>2+</sup> LBP coordination.
The Allnér and Li&Merz 12–6 parametrizations were
also tested with the TIP3P water model; the LBP was destabilized in
both cases. This illustrates the difficulty of consistently describing
different Mg<sup>2+</sup> interactions using nonpolarizable force
fields. Overall, the simulations support the hypothesis that HutP
protein becomes fully structured upon ligand binding. Subsequent RNA
binding does not affect the protein structure, in keeping with the
mechanism inferred from experimental structures
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