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Owen M.C.,Jülich Research Center | Strodel B.,Jülich Research Center | Strodel B.,Heinrich Heine University Düsseldorf | Csizmadia I.G.,University of Toronto | And 4 more authors.
Journal of Physical Chemistry B | Year: 2016

We examined the effects of Cα-centered radical formation on the stability of a model helical peptide, N-Ac-KK(AL)10KK-NH2. Three, 100 ns molecular dynamics simulations using the OPLS-AA force field were carried out on each α-helical peptide in six distinct binary TIP4P water/2,2,2-trifluoroethanol (TFE) mixtures. The α-helicity was at a maximum in 20% TFE, which was inversely proportional to the number of H-bonds between water molecules and the peptide backbone. The radial distribution of TFE around the peptide backbone was highest in 20% TFE, which enhanced helix stability. The Cα-centered radical initiated the formation of a turn within 5 ns, which was a smaller kink at high TFE concentrations, and a loop at lower TFE concentrations. The highest helicity of the peptide radical was measured in 100% TFE. The formation of hydrogen bonds between the peptide backbone and water destabilized the helix, whereas the clustering of TFE molecules around the radical center stabilized the helix. Following radical termination, the once helical structure converted to a β-sheet rich state in 100% water only, and this transition did not occur in the nonradical control peptide. This study gives evidence on how the formation of peptide radicals can initiate α-helical to β-sheet transitions under oxidative stress conditions. © 2016 American Chemical Society.

Farago E.P.,University of Szeged | Farago E.P.,CNRS Atmospheric and Combustion Chemistry Laboratory | Szori M.,University of Szeged | Szori M.,Drug Discovery Research Center | And 6 more authors.
Journal of Chemical Physics | Year: 2015

The CH3 + HO2 reaction system was studied theoretically by a newly developed, HEAT345-(Q) method based CHEAT1 protocol and includes the combined singlet and triplet potential energy surfaces. The main simplification is based on the CCSDT(Q)/cc-pVDZ calculation which is computationally inexpensive. Despite the economic and black-box treatment of higher excitations, the results are within 0.6 kcal/mol of the highly accurate literature values. Furthermore, the CHEAT1 surpassed the popular standard composite methods such as CBS-4M, CBS-QB3, CBS-APNO, G2, G3, G3MP2B3, G4, W1U, and W1BD mainly due to their poor performance in characterizing transition states (TS). For TS structures, various standard DFT and MP2 method have also been tested against the resulting CCSD/cc-pVTZ geometry of our protocol. A fairly good agreement was only found in the cases of the B2PLYP and BHandHLYP functionals, which were able to reproduce the structures of all TS studied within a maximum absolute deviation of 7%. The complex reaction mechanism was extended by three new low lying reaction channels. These are indirect water elimination from CH3OOH resulted formaldehyde, H2 elimination yielded methylene peroxide, and methanol and reactive triplet oxygen were formed via H-shift in the third channel. CHEAT1 protocol based on HEAT345-(Q) method is a robust, general, and cheap alternative for high accurate kinetic calculations. © 2015 AIP Publishing LLC.

Owen M.C.,University of Toronto | Owen M.C.,University of Szeged | Owen M.C.,NRC Steacie Institute for Molecular Sciences | Owen M.C.,Drug Discovery Research Center | And 8 more authors.
Journal of Physical Chemistry B | Year: 2012

To determine if •OH can initiate the unfolding of an amino acid residue, the elementary reaction coordinates of H abstraction by •OH different conformations (βL, γL, γD, αL, and αD) of Gly and Ala dimethyl amides were computed using first-principles quantum computations. The MPWKCIS1K/6-311++G(3df,2p)// BHandHLYP/6-311+G(d,p) level of theory was selected after different combinations of functionals and basis sets were compared. The structures of Gly and Ala in the elementary reaction steps were compared to the conformers of the Gly, Gly•, Ala, and Ala• structures in the absence of •OH/H2O, which were identified by optimizing the minima of the respective potential energy surfaces. A dramatic change in conformation is observed in the Gly and Ala conformers after conversion to Gly• and Ala•, respectively, and this change can be monitored along the minimal energy pathway. The βL conformer of Gly (-0.3 kJ mol-1) and Ala (-1.6 kJ mol-1) form the lowest-lying transition states in the reaction with •OH, whereas the side chain of Ala strongly destabilizes the α conformers compared to the γ conformers, which could cause the lower reactivity shown in Ala. This effect shown in Ala could affect the abstraction of hydrogen from Ala and the other chiral amino acid residues in the helices. The energy of subsequent hydrogen abstraction reactions between Ala• and Gly • and H2O2 remains approximately 90 kJ mol-1 below the entrance level of the •OH reaction, indicating that the •OH radical can initiate an α to β transition in an amino acid residue if a molecule such as H 2O2 can provide the hydrogen atom necessary to re-form Gly and Ala. This work delineates the mechanism of the rapid •OH- initiated unfolding of peptides and proteins which has been proposed in Alzheimer's and other peptide misfolding diseases involving amyloidogenic peptides. © 2011 American Chemical Society.

Lee D.R.,University of Szeged | Lee D.R.,University of Toronto | Galant N.J.,University of Toronto | Lee D.M.,University of Toronto | And 10 more authors.
Canadian Journal of Chemistry | Year: 2011

Noradrenaline is a neurotransmitter that is involved in various psychological processes. In the neurotransmission process, noradrenaline binds to an adrenergic receptor by forming a complex of hydrogen bonds between its two catechol ring hydroxyl groups and the amino acid residues of adrenergic receptors. Although the two catechol ring hydroxyl groups play a crucial role in making hydrogen bonds to the binding site of the adrenergic receptor, the contribution of the catechol ring hydroxyl groups to the intramolecular stability that may affect docking has not been fully studied. To reveal the specific role that the catechol ring hydroxyl groups might play in stabilizing noradrenaline, the quantum chemical computations of geometry optimization and thermodynamic functions of N-protonated noradrenaline conformers were performed at both the B3LYP/6-31G(d,p) and G3MP2B3 levels of theory, using the Gaussian 03 program. The results were compared with those of N-protonated β-hydroxy-β-phenylethylamine, which is identical to noradrenaline except it lacks two catechol ring hydroxyl groups. For the first time, post-Hartree-Fock computations were used to obtain thermodynamic functions to establish relative stabilities of all possible conformers of N-protonated noradrenaline. In this study, 18 distinct structures of N-protonated noradrenaline were revealed, and the catechol ring hydroxyl groups were found to affect noradrenaline stability positively or negatively depending on the conformational orientations. On the basis of available experimental results, the issue that the least stable conformation of two catechol ring hydroxyl groups may be involved in the docking process has been raised. These findings may be useful in synthesis of derivatives of noradrenaline in drug design. © 2011 Published by NRC Research Press.

Fiser B.,University of Szeged | Fiser B.,Drug Discovery Research Center | Szori M.,University of Szeged | Szori M.,Drug Discovery Research Center | And 9 more authors.
Journal of Physical Chemistry B | Year: 2011

All possible X-H (where X can be C, N, O or S) bond dissociation energies (BDEs) of glutathione (γ-l-glutamyl-l-cysteinyl-glycine, GSH) and its fragments have been calculated by first principle methods, and the antioxidant potential of GSH was revealed to be higher than expected in earlier studies. Electron delocalization was found to have an important influence on the antioxidant potential. All structures were optimized and their harmonic vibrational frequencies were calculated in the gas phase at the B3LYP/6-31G(d) level of theory. Solvent effects were taken into account for optimizations at the same level of theory by applying the conductor-like polarizable continuum model (CPCM). Hydrogen cleavage from glutathione proved that the G3MP2B3 composite method provides results consistent with the experimental values for bond dissociation enthalpies (DH298) of S-H, O-H, C-H, and N-H bonds. In order to replace the G3MP2B3 energies with accurate single point calculations, six density functionals, namely, MPWKCIS, MPWKCIS1K, M06, TPSS1KCIS, TPSSh, and B3LYP, were tested against G3MP2B3 for obtaining accurate bond dissociation energies. The MPWKCIS1K/6-311++G(3df,2p)//B3LYP/6-31G(d) level of theory provides the best correlation with the G3MP2B3 method for BDEs in both phases, and therefore, it is recommended for similar calculations. Gas phase results showed that the O-H bond was the weakest, while in aqueous phase the N-H bond in the ammonium group proved to have the smallest BDE value in the studied system. In both cases, the cleavage of the X-H bond was followed by decarboxylation which was responsible for the energetic preference of these processes over the S-H dissociation, which was regarded as the most favorable one until now. The calculated BDE values showed that in aqueous phase the most preferred H-abstraction site is at the weakest N-H bond (BDEaq = 349.3 kJ mol-1) in the glutamine fragment near the α-carbon. In water, the formation of N-centered radicals compared to S-centered ones (BDEaq = 351.7 kJ mol-1) is more endothermic by 2.54 kJ mol-1, due to decarboxylation. Hydrogen dissociation energies from the α-carbons are also comparable in energy with those of the thiol hydrogen, within computational error. The higher stability of the radicals-except the S-centered ones-is due to various degrees of electron delocalization. In aqueous phase, four quasi-equivalent stable radical centers (the α-carbons, the N-centered radical of the NH2 group, and the S-centered radical) were found which provide the antioxidant behavior of glutathione. © 2011 American Chemical Society.

Owen M.C.,University of Toronto | Owen M.C.,University of Szeged | Owen M.C.,Global Institute of Computational Molecular and Materials Science | Owen M.C.,Drug Discovery Research Center | And 10 more authors.
International Journal of Quantum Chemistry | Year: 2012

Selective cyclo-oxygenase-2 inhibitors (COXIBs) are prominent members of the nonsteroidal anti-inflammatory drugs. The neutral and protonated COXIB scaffold has been subjected to molecular computations in the gas phase and implicit solvent to measure the relative changes in the thermodynamic functions, enthalpy (H rel), potential energy (U rel), Gibbs free energy (G rel) and entropy (S rel) induced by selected substituents. Conformational analysis of the COXIB scaffold indentified four pairs of atropisomeric conformers (from I, I′ to IV, IV′) associated with a molecular structure containing a double rotor system. All conformers had similar stability. Para-substitution with substituents that cover a wide range of Hammett sigma values did not alter the geometries of the neutral COXIB conformers; however, the protonated COXIB scaffold was showed an increase in structural and thermodynamic perturbations due to inductive effects. Flexibility and structural resilience of the COXIB scaffold under the conditions studied herein could be an important feature of the COXIBs, especially considering the previously proposed flexibility of the cyclo-oxygenase binding site. © 2011 Wiley Periodicals, Inc.

Shin W.-J.,Yonsei University | Nam K.-Y.,Drug Discovery Research Center | Kim N.-D.,HIGH-TECH | Kim S.-H.,Yonsei University | And 4 more authors.
Chemotherapy | Year: 2016

Background: The zoonotic transmission of highly pathogenic avian influenza viruses and the global pandemic of H1N1 influenza in 2009 signified the need for a wider coverage of therapeutic options for the control of influenza. Methods: An in-house compound library was screened using a cytopathic effect inhibition assay. Selected hits were then tested in vivo and used as a core skeleton for derivative synthesis. Results: The hit compound (BMD-2601505) was effective [50% effective concentration (EC50) of 60-70 μM] in reducing the death rate of cells infected with human influenza A and B viruses as well as avian influenza A virus. Furthermore, BMD-2601505 reduced the weight loss and increased the survival after lethal infection. The compound was further modified to enhance its antiviral potency. Results show that one derivative with bromobenzene moiety was most effective (EC50 of 22-37 μM) against the influenza viruses tested. Conclusion: We identified a small benzamide compound exhibiting antiviral activity against influenza viruses. The results warrant further evaluation of antiviral activities against drug-resistant influenza isolates. © 2016 S. Karger AG, Basel.

Sheykhkarimli D.,University of Toronto | Choo K.-L.,University of Toronto | Owen M.,University of Toronto | Owen M.,University of Szeged | And 13 more authors.
Journal of Chemical Physics | Year: 2014

The epimerization of amino acid residues increases with age in living organisms. In the present study, the structural consequences and thermodynamic functions of the epimerization of thymopentin (TP-5), the active site of the thymic hormone thymopoietin, were studied using molecular dynamics and density functional theory methods. The results show that free radical-initiated D-amino acid formation is energetically favoured (-130 kJmol-1) for each residue and induces significant changes to the peptide structure. In comparison to the wild-type (each residue in the L-configuration), the radius of gyration of the D-Asp3 epimer of the peptide decreased by 0.5 Å, and disrupted the intramolecular hydrogen bonding of the native peptide. Beyond establishing important structural, energetic and thermodynamic benchmarks and reference data for the structure of TP-5, these results disseminate the understanding of molecular ageing, the epimerization of amino acid residues. © 2014 AIP Publishing LLC.

Owen M.C.,Semmelweis University | Owen M.C.,University of Szeged | Owen M.C.,Global Institute of Computational Molecular and Materials Science | Owen M.C.,Drug Discovery Research Center | And 11 more authors.
Journal of Chemical Theory and Computation | Year: 2012

Recent studies using ab initio calculations have shown that C α-centered radical formation by H-abstraction from the backbone of peptide residues has dramatic effects on peptide structure and have suggested that this reaction may contribute to the protein misfolding observed in Alzheimer's and Parkinson's diseases. To enable the effects of C α-centered radicals to be studied in longer peptides and proteins over longer time intervals, force-field parameters for the C α-centered Ala radical were developed for use with the OPLS force field by minimizing the sum of squares deviation between the quantum chemical and OPLS-AA energy hypersurfaces. These parameters were used to determine the effect of the C α-centered Ala radical on the structure of a hepta-alanyl peptide in molecular dynamics (MD) simulations. A negligible sum-of-squares energy deviation was observed in the stretching parameters, and the newly developed OPLS-AA torsional parameters showed a good agreement with the LMP2/cc-pVTZ(-f) hypersurface. The parametrization also demonstrated that derived force-field bond length and bond angle parameters can deviate from the quantum chemical equilibrium values, and that the improper torsional parameters should be developed explicitly with respect to the coupled torsional parameters. The MD simulations showed planar conformations of the C α-containing residue (Alr) are preferred and these conformations increase the formation of γ-, α-, and π-turn structures depending on the position in the turn occupied by the Alr residue. Higher-ordered structures are destabilized by Alr except when this residue occupies position "i + 1" of the 3 10-helix. These results offer new insight into the protein-misfolding mechanisms initiated by H-abstraction from the C α of peptide and protein residues. © 2012 American Chemical Society.

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