4 research outputs found
Thermodynamics of Binding of Di- and Tetrasubstituted Naphthalene Diimide Ligands to DNA GâQuadruplex
Naphthalene diimide ligands have
the potential to stabilize human
telomeric G-quadruplex DNA via noncovalent interactions. Stabilization
of G-quadruplex high order structures has become an important strategy
to develop novel anticancer therapeutics. In this study four naphthalene
diimide based ligands were analyzed in order to elucidate the principal
factors determining contributions to G-quadruplex-ligand binding.
Three possible modes of binding and their respective Gibbs free energies
for two naphthalene diimide based di-<i>N</i>-alkylpyridinium
substituted ligands have been determined using a molecular docking
technique and compared to experimental results. The structures obtained
from the molecular docking calculations, were analyzed using the ab
initio based fragment molecular orbital (FMO) method in order to determine
the major enthalpic contributions to the binding and types of interactions
between the ligand and specific residues of the G-quadruplex. A computational
methodology for the efficient and inexpensive ligand optimization
as compared to fully ab initio methods based on the estimation of
binding affinities of the naphthalene diimide derived ligands to G-quadruplex
is proposed
Accurate Prediction of Noncovalent Interaction Energies with the Effective Fragment Potential Method: Comparison of Energy Components to Symmetry-Adapted Perturbation Theory for the S22 Test Set
Noncovalent interactions play an important role in the
stabilization
of biological molecules. The effective fragment potential (EFP) is
a computationally inexpensive ab initio-based method for modeling
intermolecular interactions in noncovalently bound systems. The accuracy
of EFP is benchmarked against the S22 and S66 data sets for noncovalent
interactions [JurecÌka, P.; SÌponer, J.; CÌernyÌ,
J.; Hobza, P. <i>Phys. Chem. Chem. Phys.</i> <b>2006</b>, <i>8</i>, 1985; RÌezaÌcÌ, J.; Riley,
K. E.; Hobza, P. <i>J. Chem. Theory Comput.</i> <b>2011</b>, <i>7</i>, 2427]. The mean unsigned error (MUE) of EFP
interaction energies with respect to coupled-cluster singles, doubles,
and perturbative triples in the complete basis set limit [CCSDÂ(T)/CBS]
is 0.9 and 0.6 kcal/mol for S22 and S66, respectively, which is similar
to the MUE of MP2 and SCS-MP2 for the same data sets, but with a greatly
reduced computational expense. Moreover, EFP outperforms classical
force fields and popular DFT functionals such as B3LYP and PBE, while
newer dispersion-corrected functionals provide a more accurate description
of noncovalent interactions. Comparison of EFP energy components with
the symmetry-adapted perturbation theory (SAPT) energies for the S22
data set shows that the main source of errors in EFP comes from Coulomb
and polarization terms and provides a valuable benchmark for further
improvements in the accuracy of EFP and force fields in general
Extension of the Effective Fragment Potential Method to Macromolecules
The
effective fragment potential (EFP) approach, which can be described
as a nonempirical polarizable force field, affords an accurate first-principles
treatment of noncovalent interactions in extended systems. EFP can
also describe the effect of the environment on the electronic properties
(e.g., electronic excitation energies and ionization and electron-attachment
energies) of a subsystem via the QM/EFP (quantum mechanics/EFP) polarizable
embedding scheme. The original formulation of the method assumes that
the system can be separated, without breaking covalent bonds, into
closed-shell fragments, such as solvent and solute molecules. Here,
we present an extension of the EFP method to macromolecules (mEFP).
Several schemes for breaking a large molecule into small fragments
described by EFP are presented and benchmarked. We focus on the electronic
properties of molecules embedded into a protein environment and consider
ionization, electron-attachment, and excitation energies (single-point
calculations only). The model systems include chromophores of green
and red fluorescent proteins surrounded by several nearby amino acid
residues and phenolate bound to the T4 lysozyme. All mEFP schemes
show robust performance and accurately reproduce the reference full
QM calculations. For further applications of mEFP, we recommend either
the scheme in which the peptide is cut along the C<sub>α</sub>âC bond, giving rise to one fragment per amino acid, or the
scheme with two cuts per amino acid, along the C<sub>α</sub>âC and C<sub>α</sub>âN bonds. While using these
fragmentation schemes, the errors in solvatochromic shifts in electronic
energy differences (excitation, ionization, electron detachment, or
electron-attachment) do not exceed 0.1 eV. The largest error of QM/mEFP
against QM/EFP (no fragmentation of the EFP part) is 0.06 eV (in most
cases, the errors are 0.01â0.02 eV). The errors in the QM/molecular
mechanics calculations with standard point charges can be as large
as 0.3 eV
Conformationally Locked Chromophores as Models of Excited-State Proton Transfer in Fluorescent Proteins
Members of the green fluorescent protein (GFP) family
form chromophores
by modifications of three internal amino acid residues. Previously,
many key characteristics of chromophores were studied using model
compounds. However, no studies of intermolecular excited-state proton
transfer (ESPT) with GFP-like synthetic chromophores have been performed
because they either are nonfluorescent or lack an ionizable OH group.
In this paper we report the synthesis and photochemical study of two
highly fluorescent GFP chromophore analogues: <i>p</i>-HOBDI-BF2
and <i>p</i>-HOPyDI:Zn. Among known fluorescent compounds, <i>p</i>-HOBDI-BF<sub>2</sub> is the closest analogue of the native
GFP chromophore. These irrreversibly (<i>p</i>-HOBDI-BF<sub>2</sub>) and reversibly (<i>p</i>-HOPyDI:Zn) locked compounds
are the first examples of fully planar GFP chromophores, in which
photoisomerization-induced deactivation is suppressed and protolytic
photodissociation is observed. The photophysical behavior of <i>p</i>-HOBDI-BF2 and <i>p</i>-HOPyDI:Zn (excited state
p<i>K</i><sub>a</sub>âs, solvatochromism, kinetics,
and thermodynamics of proton transfer) reveals their high photoacidity,
which makes them good models of intermolecular ESPT in fluorescent
proteins. Moreover, <i>p</i>-HOPyDI:Zn is a first example
of âsuperâ photoacidity in metalâorganic complexes