15 research outputs found
Theoretical investigation of thiophene-linked porphyrin-perylene photosensitiser for bulk-heterojunction solar cells
<p>In this work, quantum chemical calculations were applied to investigate a new series of porphyrin-perylene conjugates for their potential use as light-harvesting compounds in bulk-heterojunction solar cells. Molecular design relies on the integration of a electron-donating porphyrin and a electron-accepting perylene units via a spacer containing 0 to 10 thiophene rings. Electronic properties of these push–pull systems were studied using density functional theory (DFT) and time-dependent DFT approaches. Results show that introduction of thiophene-based spacer with different number of the thiophene rings significantly affects the electronic and absorption properties of the molecules. According to its suitable energy gap, efficient charge transfer and appropriate absorption behaviour determined by the calculation, the derivative having a terthiophene linker should be as the optimal compound among all molecules studied herein.</p
Effect of Halogen Substitutions on dUMP to Stability of Thymidylate Synthase/dUMP/mTHF Ternary Complex Using Molecular Dynamics Simulation
The stability of the thymidylate
synthase (TS)/2-deoxyuridine-5-monophosphate
(dUMP)/5,10-methylene-5,6,7,8-tetrahydrofolate (mTHF) ternary complex
formation and Michael addition are considered as important steps that
are involved in the inhibition mechanism of the anticancer prodrug
5-fluorouracil (5-FU). Here, the effect of three different halogen
substitutions on the C-5 position of the dUMP (XdUMPs = FdUMP, CldUMP,
and BrdUMP), the normal substrate, on the stability of the TS/dUMP
and TS/dUMP/mTHF binary and ternary complexes, respectively, was investigated
via molecular dynamics simulation. The simulated results revealed
that the stability of all the systems was substantially increased
by mTHF binding to the catalytic pocket. In the ternary complex, a
much greater stabilization of the dUMP and XdUMPs through electrostatic
interactions, including charge–charge and hydrogen bond interactions,
was found compared to mTHF. An additional unique hydrogen bond between
the substituted fluorine of FdUMP and the hydroxyl group of the TS
Y94 residue was observed in both the binary and ternary complexes.
The distance between the S<sup>–</sup> atom of the TS C146
residue and the C6 atom of dUMP, at <4 Ã… in all systems, suggested
that a Michael addition with the formation of a S–C6 covalent
bond potentially occurred, although the hydrogen atom on C6 of dUMP
is substituted by a halogen atom. The MM/PBSA binding free energy
revealed the significant role of the bridging waters around the ligands
in the increased binding affinity (∼10 kcal/mol) of dUMP/XdUMP,
either alone or together with mTHF, toward TS. The order of the averaged
binding affinity in the ternary systems was found to be CldUMP ≈
FdUMP > dUMP > BrdUMP, suggesting that CldUMP could be a potent
candidate
TS inhibitor, the same as FdUMP (the metabolite form of 5-FU)
High-Level QM/MM Calculations Support the Concerted Mechanism for Michael Addition and Covalent Complex Formation in Thymidylate Synthase
Thymidylate synthase (TS) is a promising
cancer target, due to its crucial function in thymine synthesis. It
performs the reductive methylation of 2′-deoxyuridine-5′-phosphate
(dUMP) to thymidine-5′-phosphate (dTMP), using <i>N</i>-5,10-methylene-5,6,7,8-tetrahydrofolate (mTHF) as a cofactor. After
the formation of the dUMP/mTHF/TS noncovalent complex, and subsequent
conformational activation, this complex has been proposed to react
via nucleophilic attack (Michael addition) by Cys146, followed by
methylene-bridge formation to generate the ternary covalent intermediate.
Herein, QM/MM (B3LYP-D/6-31+GÂ(d)-CHARMM27) methods are used to model
the formation of the ternary covalent intermediate. A two-dimensional
potential energy surface reveals that the methylene-bridged intermediate
is formed via a concerted mechanism, as indicated by a single transition
state on the minimum energy pathway and the absence of a stable enolate
intermediate. A range of different QM methods (B3LYP, MP2 and SCS-MP2,
and different basis sets) are tested for the calculation of the activation
energy barrier for the formation of the methylene-bridged intermediate.
We test convergence of the QM/MM results with respect to size of the
QM region. Inclusion of Arg166, which interacts with the nucleophilic
thiolate, in the QM region is important for reliable results; the
MM model apparently does not reproduce energies for distortion of
the guanidinium side chain correctly. The spin component scaled-Møller–Plessett
perturbation theory (SCS-MP2) approach was shown to be in best agreement
(within 1.1 kcal/mol) while the results obtained with MP2 and B3LYP
also yielded acceptable values (deviating by less than 3 kcal/mol)
compared with the barrier derived from experiment. Our results indicate
that using a dispersion-corrected DFT method, or a QM method with
an accurate treatment of electron correlation, increases the agreement
between the calculated and experimental activation energy barriers,
compared with the semiempirical AM1 method. These calculations provide
important insight into the reaction mechanism of TS and may be useful
in the design of new TS inhibitors
Molecular Dynamics Simulations of the Interaction of Beta Cyclodextrin with a Lipid Bilayer
Beta cyclodextrin
(βCD) is well-known as a potent drug carrier
improving drug solubility, stability, and bioavailability. The water
layer adjacent to the membrane surface and lipophilic domain itself
are a controlling barrier for drug transport. However, the molecular
details of the interaction between βCD and the lipid membrane
has not yet been clearly explained. Here, molecular dynamics simulations
were performed to visualize the interaction process of the βCD
molecule with the lipid bilayer for six microseconds in total. Our
results show that βCD passively diffuses into the lipid bilayer
by pointing its open secondary rim toward the lipid polar groups and
then remains at the phosphate and glycerol-ester groups with hydrogen
bond formation. The information obtained from this study may suggest
that the association of βCD at the cellular membrane plays an
important role for the transfer of drug and the extraction of cholesterol
Long Time Scale GPU Dynamics Reveal the Mechanism of Drug Resistance of the Dual Mutant I223R/H275Y Neuraminidase from H1N1-2009 Influenza Virus
Multidrug resistance of the pandemic H1N1-2009 strain
of influenza has been reported due to widespread treatment using the
neuraminidase (NA) inhibitors, oseltamivir (Tamiflu), and zanamivir
(Relenza). From clinical data, the single I223R (IR) mutant of H1N1-2009 NA reduced efficacy of oseltamivir
and zanamivir by 45 and 10 times, respectively.
More seriously, the efficacy of these two inhibitors against the double
mutant I223R/H275Y (IRHY) was significantly
reduced by a factor of 12 374 and 21 times, respectively, compared
to the wild-type. This has led to the
question of why the efficacy of the NA inhibitors is reduced by the
occurrence of these mutations and, specifically, why the efficacy
of oseltamivir against the double mutant IRHY was significantly reduced,
to the point where oseltamivir has become an ineffective treatment.
In this study, 1 μs of molecular dynamics (MD) simulations was
performed to answer these questions. The simulations, run using graphical
processors (GPUs), were used to investigate the effect of conformational
change upon binding of the NA inhibitors oseltamivir and zanamivir
in the wild-type and the IR and IRHY mutant strains. These long time
scale dynamics simulations demonstrated that the mechanism of resistance
of IRHY to oseltamivir was due to the loss of key hydrogen bonds between
the inhibitor and residues in the 150-loop. This allowed NA to transition
from a closed to an open conformation. Oseltamivir binds weakly with
the open conformation of NA due to poor electrostatic interactions
between the inhibitor and the active site. The results suggest that
the efficacy of oseltamivir is reduced significantly because of conformational
changes that lead to the open form of the 150-loop. This suggests
that drug resistance could be overcome by increasing hydrogen bond
interactions between NA inhibitors and residues in the 150-loop, with
the aim of maintaining the closed conformation, or by designing inhibitors
that can form a hydrogen bond to the mutant R223 residue, thereby
preventing competition between R223 and R152
Long Time Scale GPU Dynamics Reveal the Mechanism of Drug Resistance of the Dual Mutant I223R/H275Y Neuraminidase from H1N1-2009 Influenza Virus
Multidrug resistance of the pandemic H1N1-2009 strain
of influenza has been reported due to widespread treatment using the
neuraminidase (NA) inhibitors, oseltamivir (Tamiflu), and zanamivir
(Relenza). From clinical data, the single I223R (IR) mutant of H1N1-2009 NA reduced efficacy of oseltamivir
and zanamivir by 45 and 10 times, respectively.
More seriously, the efficacy of these two inhibitors against the double
mutant I223R/H275Y (IRHY) was significantly
reduced by a factor of 12 374 and 21 times, respectively, compared
to the wild-type. This has led to the
question of why the efficacy of the NA inhibitors is reduced by the
occurrence of these mutations and, specifically, why the efficacy
of oseltamivir against the double mutant IRHY was significantly reduced,
to the point where oseltamivir has become an ineffective treatment.
In this study, 1 μs of molecular dynamics (MD) simulations was
performed to answer these questions. The simulations, run using graphical
processors (GPUs), were used to investigate the effect of conformational
change upon binding of the NA inhibitors oseltamivir and zanamivir
in the wild-type and the IR and IRHY mutant strains. These long time
scale dynamics simulations demonstrated that the mechanism of resistance
of IRHY to oseltamivir was due to the loss of key hydrogen bonds between
the inhibitor and residues in the 150-loop. This allowed NA to transition
from a closed to an open conformation. Oseltamivir binds weakly with
the open conformation of NA due to poor electrostatic interactions
between the inhibitor and the active site. The results suggest that
the efficacy of oseltamivir is reduced significantly because of conformational
changes that lead to the open form of the 150-loop. This suggests
that drug resistance could be overcome by increasing hydrogen bond
interactions between NA inhibitors and residues in the 150-loop, with
the aim of maintaining the closed conformation, or by designing inhibitors
that can form a hydrogen bond to the mutant R223 residue, thereby
preventing competition between R223 and R152
Comparison of Implicit and Explicit Solvation Models for <i>Iota</i>-Cyclodextrin Conformation Analysis from Replica Exchange Molecular Dynamics
Large
ring cyclodextrins have become increasingly important for
drug delivery applications. In this work, we have performed replica-exchange
molecular dynamics simulations using both implicit and explicit water
solvation models to study the conformational diversity of <i>iota</i>-cyclodextrin containing 14 α-1,4 glycosidic linked d-glucopyranose units (CD14). The new quantifiable calculation
methods are proposed to analyze the openness, bending, and twisted
conformation of CD14 in terms of circularity, biplanar angle, and
one-directional conformation (ODC). CD14 in GB implicit water model
(Igb5) was found mostly in an opened conformation with average circularity
of 0.39 ± 0.16 and a slight bend with average biplanar angle
of 145.5 ± 16.0°. In contrast, CD14 in TIP3P explicit water
solvation is significantly twisted with average circularity of 0.16 ±
0.10, while 29.1% are ODCs. In addition, classification of CD14 conformations
using a Gaussian mixture model (GMM) shows that 85.0% of all CD14
in implicit water at 300 K correspond to the elliptical conformation,
in contrast to 82.3% in twisted form in explicit water. GMM clustering
also reveals minority conformations of CD14 such as the 8-shape, boat-form,
and twisted conformations. This work provides fundamental insights
into CD14 conformation, influence of solvation models, and also proposes
new quantifiable analysis techniques for molecular conformation studies
in the future
Molecular Dynamics Simulation Reveals the Selective Binding of Human Leukocyte Antigen Alleles Associated with Behçet's Disease
<div><p>Behçet’s disease (BD), a multi-organ inflammatory disorder, is associated with the presence of the human leukocyte antigen (HLA) HLA-B*51 allele in many ethnic groups. The possible antigen involvement of the major histocompatibility complex class I chain related gene A transmembrane (MICA-TM) nonapeptide (AAAAAIFVI) has been reported in BD symptomatic patients. This peptide has also been detected in HLA-A*26:01 positive patients. To investigate the link of BD with these two specific HLA alleles, molecular dynamics (MD) simulations were applied on the MICA-TM nonapeptide binding to the two BD-associated HLA alleles in comparison with the two non-BD-associated HLA alleles (B*35:01 and A*11:01). The MD simulations were applied on the four HLA/MICA-TM peptide complexes in aqueous solution. As a result, stabilization for the incoming MICA-TM was found to be predominantly contributed from van der Waals interactions. The P2/P3 residue close to the N-terminal and the P9 residue at the C-terminal of the MICA-TM nonapeptide served as the anchor for the peptide accommodated at the binding groove of the BD associated HLAs. The MM/PBSA free energy calculation predicted a stronger binding of the HLA/peptide complexes for the BD-associated HLA alleles than for the non-BD-associated ones, with a ranked binding strength of B*51:01 > B*35:01 and A*26:01 > A*11:01. Thus, the HLAs associated with BD pathogenesis expose the binding efficiency with the MICA-TM nonapeptide tighter than the non-associated HLA alleles. In addition, the residues 70, 73, 99, 146, 147 and 159 of the two BD-associated HLAs provided the conserved interaction for the MICA-TM peptide binding.</p></div
Decomposition energy per HLA residue fingerprint plots.
<p>The HLA contribution to the MICA-TM binding is shown in terms of the electrostatic (ele) and van der Waals (vdW) interactions.</p
Hydrogen bond interactions.
<p>The percentage occupancy of H-bonds averaged over the last 25 ns of simulation time between the nine residues (P1–P9) of the MICA-TM peptide and the HLA residues for the four complexes.</p