3 research outputs found
Channeling through Two Stacked Guanine Quartets of One and Two Alkali Cations in the Li<sup>+</sup>, Na<sup>+</sup>, K<sup>+</sup>, and Rb<sup>+</sup> Series. Assessment of the Accuracy of the SIBFA Anisotropic Polarizable Molecular Mechanics Potential
Stacking
of guanine quartets (GQs) can trigger the formation of
DNA or RNA quadruple helices, which play numerous biochemical roles.
The GQs are stabilized by alkali cations, mainly K<sup>+</sup> and
Na<sup>+</sup>, which can reside in, or channel through, the central
axis of the GQ stems. Further, ion conduction through GQ wires can
be leveraged for nanochemistry applications. G-quadruplex systems
have been extensively studied by classical molecular dynamics (MD)
simulations using pair-additive force fields or by quantum-chemical
(QC) calculations. However, the non-polarizable force fields are very
approximate, while QC calculations lack the necessary sampling. Thus,
ultimate description of GQ systems would require long-enough simulations
using advanced polarizable molecular mechanics (MM). However, to perform
such calculations, it is first mandatory to evaluate the method’s
accuracy using benchmark QC. We report such an evaluation for SIBFA
polarizable MM, bearing on the channeling (movement) of an alkali
cation (Li<sup>+</sup>, Na<sup>+</sup>, K<sup>+</sup>, or Rb<sup>+</sup>) along the axis of two stacked G quartets interacting with either
one or two ions. The QC energy profiles display markedly different
features depending upon the cation but can be retrieved in the majority
of cases by the SIBFA profiles. An appropriate balance of first-order
(electrostatic and short-range repulsion) and second-order (polarization,
charge-transfer, and dispersion) contributions within Δ<i>E</i> is mandatory. With two cations in the channel, the relative
weights of the second-order contributions increase steadily upon increasing
the ion size. In the G8 complexes with two K<sup>+</sup> or two Rb<sup>+</sup> cations, the sum of polarization and charge-transfer exceeds the first order terms for all ion positions
Stacked and H-bonded cytosine dimers. Analysis of the intermolecular interaction energies by parallel quantum chemistry and polarizable molecular mechanics.
International audienceUntil now, atomistic simulations of DNA and RNA and their complexes have been executed using well calibrated but conceptually simple pair-additive empirical potentials (force fields). Although such simulations provided many valuable results, it is well established that simple force fields also introduce errors into the description, underlying the need for development of alternative anisotropic, polarizable molecular mechanics (APMM) potentials. One of the most abundant forces in all kinds of nucleic acids topologies is base stacking. Intra- and interstrand stacking is assumed to be the most essential factor affecting local conformational variations of B-DNA. However, stacking also contributes to formation of all kinds of noncanonical nucleic acids structures, such as quadruplexes or folded RNAs. The present study focuses on 14 stacked cytosine (Cyt) dimers and the doubly H-bonded dimer. We evaluate the extent to which an APMM procedure, SIBFA, could account quantitatively for the results of high-level quantum chemistry (QC) on the total interaction energies, and the individual energy contributions and their nonisotropic behaviors. Good agreements are found at both uncorrelated HF and correlated DFT and CCSD(T) levels. Resorting in SIBFA to distributed QC multipoles and to an explicit representation of the lone pairs is essential to respectively account for the anisotropies of the Coulomb and of the exchange-repulsion QC contributions
Calibration of 1,2,4-Triazole-3-Thione, an Original Zn-Binding Group of Metallo-β-Lactamase Inhibitors. Validation of a Polarizable MM/MD Potential by Quantum Chemistry
In the context of the SIBFA polarizable
molecular mechanics/dynamics (PMM/PMD) procedure, we report the calibration
and a series of validation tests for the 1,2,4-triazole-3-thione (TZT)
heterocycle. TZT acts as the chelating group of inhibitors of dizinc
metallo-β-lactamases (MBL), an emerging class of Zn-dependent
bacterial enzymes, which by cleaving the β-lactam bond of most
β-lactam antibiotics are responsible for the acquired resistance
of bacteria to these drugs. Such a study is indispensable prior to
performing PMD simulations of complexes of TZT-based inhibitors with
MBL’s, on account of the anchoring role of TZT in the dizinc
MBL recognition site. Calibration was done by comparisons to energy
decomposition analyses (EDA) of high-level <i>ab initio</i> QC computations of the TZT complexes with two probes: Zn(II), representative
of “soft” dications, and water, representative of dipolar
molecules. We performed distance variations of the approach of each
probe to each of the two TZT atoms involved in Zn ligation, the S
atom and the N atom <i>ortho</i> to it, so that each SIBFA
contribution matches its QC counterpart. Validations were obtained
by performing in- and out-of-plane angular variations of Zn(II) binding
in monoligated Zn(II)–TZT complexes. The most demanding part
of this study was then addressed. How well does Δ<i>E</i>(SIBFA) and its individual contributions compare to their QC counterparts
in the dizinc binding site of one MBL, L1, whose structure is known
from high-resolution X-ray crystallography? Six distinct complexes
were considered, namely each separate monozinc site, and the dizinc
site, whether ligated or unligated by TZT. Despite the large magnitude
of the interaction energies, in all six complexes Δ<i>E</i>(SIBFA) can match Δ<i>E</i>(QC) with relative errors
<2% and the proper balance of individual energy contributions.
The computations were extended to the dizinc site of another MBL,
VIM-2, and its complexes with two other TZT analogues. Δ<i>E</i>(SIBFA) faithfully reproduced Δ<i>E</i>(QC) in terms of magnitude, ranking of the three ligands, and trends
of the separate energy contributions. A preliminary extension to correlated
calculations is finally presented. All these validations should enable
a secure design of a diversity of TZT-containing MBL inhibitors: a
structurally and energetically correct anchoring of TZT should enable
all other inhibitor groups to in turn optimize their interactions
with the other target MBL residues