Journal of Physical Organic Chemistry, Jan 5, 2022
Three distinct procedures for obtaining the effective Gibbs energies of activation from computed ... more Three distinct procedures for obtaining the effective Gibbs energies of activation from computed energies for a reaction involving multiple reactant-state (RS) and transition-state (TS) conformers are shown to be equivalent. If Boltzmann-weighted average Gibbs energies for RS and TS are evaluated, then the Gibbs energy contribution from entropy of mixing of both RS and TS conformers must also be included in order to obtain the correct value for the effective Gibbs energy of activation. Application to a solvolytic reaction of 4,4'-dimethoxybenzhydrylpyridinium cation, which is shown to satisfy the Curtin-Hammett principle with rapid interconversion of RS conformers, demonstrates the use of each procedure for evaluation of the effective Gibbs energy of activation.
ChemInform Abstract Auf der Basis eines " simple valence force field (SVF F)" wird ein Modell zur... more ChemInform Abstract Auf der Basis eines " simple valence force field (SVF F)" wird ein Modell zur Berechnung von NPE-Effekten entwickelt. Damit werden Schwingungsfrequenzen und thermodynamische Daten für Alkane und Alkylhalogenide berechnet, bei Annahme von Bedingungen des idealen Gases. Die Methode ist auf andere Molekülarten und Zustände erweiterbar.
Page 1. Transition-state structural reÐnement with GRACE and CHARMM: Flexible QM/MM modelling for... more Page 1. Transition-state structural reÐnement with GRACE and CHARMM: Flexible QM/MM modelling for lactate dehydrogenase Alexander J. Turner, Vicente Moliner and Ian H. Williams* Department of Chemistry, University of Bath, Bath, UK BA2 7AY ...
Computational exploration of α-lactone rearrangements and the cyclic halonium zwitterion from bro... more Computational exploration of α-lactone rearrangements and the cyclic halonium zwitterion from bromination of acrylate anion in water: implicit vs. explicit solvation.
The structure and dynamics of B. circulans β-1,4-xylanase (BCX) were comparatively studied utiliz... more The structure and dynamics of B. circulans β-1,4-xylanase (BCX) were comparatively studied utilizing molecular dynamics.
Journal of the American Chemical Society, Feb 20, 2018
The origin of enzyme catalysis remains a question of debate despite much intense study. We report... more The origin of enzyme catalysis remains a question of debate despite much intense study. We report a QM/MM theoretical study of the S N 2 methyl transfer reaction catalyzed by a glycine N-methyltransferase (GNMT) and three mutants to test whether recent experimental observations of rate-constant reductions and variations in inverse secondary α-3 H kinetic isotope effects (KIEs) should be attributed to changes in the methyl donor−acceptor distance (DAD): is catalysis due to a compression effect? Semiempirical (AM1) and DFT (M06-2X) methods were used to describe the QM subset of atoms, while OPLS-AA and TIP3P classical force fields were used for the protein and water molecules, respectively. The computed activation free energies and KIEs are in good agreement with experimental data, but the mutations do not meaningfully affect the DAD: compression cannot explain the experimental variations on KIEs. On the contrary, electrostatic properties in the active site correlate with the catalytic activity of wild type and mutants. The plasticity of the enzyme moderates the effects of the mutations, explaining the rather small degree of variation in KIEs and reactivities.
The glucagon-like peptide 1 receptor (GLP-1R) is a member of the family (or class) B G-protein-co... more The glucagon-like peptide 1 receptor (GLP-1R) is a member of the family (or class) B G-protein-coupled receptor (GPCR). The receptor is a regulator of insulin and a key target in treating Type 2 diabetes mellitus. In this investigation, computational chemistry techniques such as molecular docking were combined with in silico ADME/Tox predictions to determine the position and structure of the allosteric binding site, as well as to examine how the allosteric modulators bind to the binding site. In silico evaluation was used to evaluate the ADME/Tox properties of the allosteric modulators. The findings of the ligand docking studies suggest that the allosteric binding site is situated around the transmembrane (TM) domain TM 6 of the receptor in the active state. ADME/Tox characterisation of the allosteric modulators demonstrate that compounds 1–3 (2,6,7-trichloro-3-(trifluoromethyl)quinoxaline, 1-(5-(4-(tert-butyl)phenyl)-1,3,4-oxadiazol-2-yl)-6,6-dimethyl-3-(methylsulfonyl)-6,7-dihydro...
Journal of physics. Condensed matter : an Institute of Physics journal, Mar 17, 2018
A quasi two-dimensional colloidal suspension is studied under the influence of immobilisation (pi... more A quasi two-dimensional colloidal suspension is studied under the influence of immobilisation (pinning) of a random fraction of its particles. We introduce a novel experimental method to perform random pinning and, with the support of numerical simulation, we find that increasing the pinning concentration smoothly arrests the system, with a cross-over from a regime of high mobility and high entropy to a regime of low mobility and low entropy. At the local level, we study fluctuations in area fraction and concentration of pins and map them to entropic structural signatures and local mobility, obtaining a measure for the local entropic fluctuations of the experimental system.
Kinetic isotope effects have been computed for the Claisen rearrangement of chorismate to prephen... more Kinetic isotope effects have been computed for the Claisen rearrangement of chorismate to prephenate in aqueous solution and in the active site of chorismate mutase from B. subtilus. These included primary 13C and 18O and secondary 3H effects for substitutions at the bond-making and bond-breaking positions. The initial structures of the putative stationary points on the potential energy surface, required for the calculations of isotope effects using the CAMVIB/CAMISO programs, have been selected from hybrid QM/MM molecular dynamical simulations using the DYNAMO program. Refinement of the reactant complex and transition-state structures has been carried out by means of AM1/CHARMM24/TIP3P calculations using the GRACE program, with full gradient relaxation of the position of > 5200 atoms for the enzymic simulations, and with a box containing 711 water molecules for the corresponding reaction in aqueous solution. Comparison of these results, and of gas phase calculations, with experimental data has shown that the chemical rearrangement is largely rate-determining for the enzyme mechanism. Inclusion of the chorismate conformational pre-equilibrium step in the modelled kinetic scheme leads to better agreement between recent experimental data and theoretical predictions. These results provide new information on an important enzymatic transformation, and the key factors responsible for the kinetics of its molecular mechanism are clarified. Treatment of the enzyme and/or solvent environment by means of a large and flexible model is absolutely essential for prediction of kinetic isotope effects.
The G-protein coupled receptors (GPCRs) superfamily comprise similar proteins arranged into famil... more The G-protein coupled receptors (GPCRs) superfamily comprise similar proteins arranged into families or classes thus making it one of the largest in the mammalian genome.
In 1997, a collection of twenty personal perspectives from eminent chemists was published in Pure... more In 1997, a collection of twenty personal perspectives from eminent chemists was published in Pure and Applied Chemistry to mark the centenary of physical organic chemistry [1]. This Symposium in Print, entitled Physical Organic Chemistry in the 21st Century (POC21C), was organized by the IUPAC Commission on Physical Organic Chemistry, which was chaired at that time by Tom Tidwell, who contributed a historical prologue in which he suggested Stieglitz’s 1899 proposal of carbocations as reaction intermediates as (unwittingly) having given birth to the discipline. The principal authors were Edward Arnett, Daniel Bellus, Ron Breslow, Fulvio Cacace, Jan Engberts, Marye Anne Fox, Ken Houk, Keith Ingold, Alan Katritzky, Ed Kosower, Meir Lahav, Teruaki Mukaiyama, Oleg Nefedov, George Olah, John Roberts, Jean-Michel Savéant, Helmut Schwarz, Andrew Streitwieser, Frank Westheimer, and Akio Yamamoto. Tidwell noted that, whereas they were not all known as physical organic chemists, yet they had a...
Journal of the Chemical Society, Chemical Communications, 1986
Calculations for [2H1]cyclohexane with a scaled quantum-mechanical 3-21G force field indicate a p... more Calculations for [2H1]cyclohexane with a scaled quantum-mechanical 3-21G force field indicate a preference for equatorial deuterium in accord with experiment but contrary to expectation.
Spectrochimica Acta Part A: Molecular Spectroscopy, 1992
The fundamental IR vibrational modes of trifluoroacetyl fluoride CF3C(O)F and trifluoroacetyl chl... more The fundamental IR vibrational modes of trifluoroacetyl fluoride CF3C(O)F and trifluoroacetyl chloride CF3C(O)CI have been reexamined by ab initio molecular orbital calculations and compared with literature assignments. Several bands of the IR spectrum are reassigned. The Q-branch and integrated absorption cross-sections have been measured for vl, v3, 1,4 and v~l fundamental bands for both pressurized and unpressurized samples on each molecule. The UV absorption spectra of CF3C(O)F and CF3C(O)CI show a structureless continuum with a maximum at 210 nm (Omax = 3.20+0.02 x 10-2°cm 2 molecule-~) and 255 nm (Om~ = 7.66 + 0.26 X 10-2o cm 2 molecule-l), respectively. The nature of the electronic transition giving rise to the UV absorption spectrum for CF3C(O)F and CF3C(O)CI has been examined by ab initio molecular orbital calculations. It is attributed to the/[ IA"~-~tA' electronic transition.
Journal of the Chemical Society, Perkin Transactions 2, 1995
... John Wilkie and Ian H. Williams* School of Chemistry, University of Bath, Bath, UK BA2 7A Y .... more ... John Wilkie and Ian H. Williams* School of Chemistry, University of Bath, Bath, UK BA2 7A Y ... Methoxide-formaldeh yde b*d HF/3-2 1 G 2.662 I .420 139.2 HF/6-3 1 G ... Dih y dr op yridine-for maldeh y de-imidazolium Replacement of ammonium by imidazolium as the proton donor ...
Journal of Physical Organic Chemistry, Jan 5, 2022
Three distinct procedures for obtaining the effective Gibbs energies of activation from computed ... more Three distinct procedures for obtaining the effective Gibbs energies of activation from computed energies for a reaction involving multiple reactant-state (RS) and transition-state (TS) conformers are shown to be equivalent. If Boltzmann-weighted average Gibbs energies for RS and TS are evaluated, then the Gibbs energy contribution from entropy of mixing of both RS and TS conformers must also be included in order to obtain the correct value for the effective Gibbs energy of activation. Application to a solvolytic reaction of 4,4'-dimethoxybenzhydrylpyridinium cation, which is shown to satisfy the Curtin-Hammett principle with rapid interconversion of RS conformers, demonstrates the use of each procedure for evaluation of the effective Gibbs energy of activation.
ChemInform Abstract Auf der Basis eines " simple valence force field (SVF F)" wird ein Modell zur... more ChemInform Abstract Auf der Basis eines " simple valence force field (SVF F)" wird ein Modell zur Berechnung von NPE-Effekten entwickelt. Damit werden Schwingungsfrequenzen und thermodynamische Daten für Alkane und Alkylhalogenide berechnet, bei Annahme von Bedingungen des idealen Gases. Die Methode ist auf andere Molekülarten und Zustände erweiterbar.
Page 1. Transition-state structural reÐnement with GRACE and CHARMM: Flexible QM/MM modelling for... more Page 1. Transition-state structural reÐnement with GRACE and CHARMM: Flexible QM/MM modelling for lactate dehydrogenase Alexander J. Turner, Vicente Moliner and Ian H. Williams* Department of Chemistry, University of Bath, Bath, UK BA2 7AY ...
Computational exploration of α-lactone rearrangements and the cyclic halonium zwitterion from bro... more Computational exploration of α-lactone rearrangements and the cyclic halonium zwitterion from bromination of acrylate anion in water: implicit vs. explicit solvation.
The structure and dynamics of B. circulans β-1,4-xylanase (BCX) were comparatively studied utiliz... more The structure and dynamics of B. circulans β-1,4-xylanase (BCX) were comparatively studied utilizing molecular dynamics.
Journal of the American Chemical Society, Feb 20, 2018
The origin of enzyme catalysis remains a question of debate despite much intense study. We report... more The origin of enzyme catalysis remains a question of debate despite much intense study. We report a QM/MM theoretical study of the S N 2 methyl transfer reaction catalyzed by a glycine N-methyltransferase (GNMT) and three mutants to test whether recent experimental observations of rate-constant reductions and variations in inverse secondary α-3 H kinetic isotope effects (KIEs) should be attributed to changes in the methyl donor−acceptor distance (DAD): is catalysis due to a compression effect? Semiempirical (AM1) and DFT (M06-2X) methods were used to describe the QM subset of atoms, while OPLS-AA and TIP3P classical force fields were used for the protein and water molecules, respectively. The computed activation free energies and KIEs are in good agreement with experimental data, but the mutations do not meaningfully affect the DAD: compression cannot explain the experimental variations on KIEs. On the contrary, electrostatic properties in the active site correlate with the catalytic activity of wild type and mutants. The plasticity of the enzyme moderates the effects of the mutations, explaining the rather small degree of variation in KIEs and reactivities.
The glucagon-like peptide 1 receptor (GLP-1R) is a member of the family (or class) B G-protein-co... more The glucagon-like peptide 1 receptor (GLP-1R) is a member of the family (or class) B G-protein-coupled receptor (GPCR). The receptor is a regulator of insulin and a key target in treating Type 2 diabetes mellitus. In this investigation, computational chemistry techniques such as molecular docking were combined with in silico ADME/Tox predictions to determine the position and structure of the allosteric binding site, as well as to examine how the allosteric modulators bind to the binding site. In silico evaluation was used to evaluate the ADME/Tox properties of the allosteric modulators. The findings of the ligand docking studies suggest that the allosteric binding site is situated around the transmembrane (TM) domain TM 6 of the receptor in the active state. ADME/Tox characterisation of the allosteric modulators demonstrate that compounds 1–3 (2,6,7-trichloro-3-(trifluoromethyl)quinoxaline, 1-(5-(4-(tert-butyl)phenyl)-1,3,4-oxadiazol-2-yl)-6,6-dimethyl-3-(methylsulfonyl)-6,7-dihydro...
Journal of physics. Condensed matter : an Institute of Physics journal, Mar 17, 2018
A quasi two-dimensional colloidal suspension is studied under the influence of immobilisation (pi... more A quasi two-dimensional colloidal suspension is studied under the influence of immobilisation (pinning) of a random fraction of its particles. We introduce a novel experimental method to perform random pinning and, with the support of numerical simulation, we find that increasing the pinning concentration smoothly arrests the system, with a cross-over from a regime of high mobility and high entropy to a regime of low mobility and low entropy. At the local level, we study fluctuations in area fraction and concentration of pins and map them to entropic structural signatures and local mobility, obtaining a measure for the local entropic fluctuations of the experimental system.
Kinetic isotope effects have been computed for the Claisen rearrangement of chorismate to prephen... more Kinetic isotope effects have been computed for the Claisen rearrangement of chorismate to prephenate in aqueous solution and in the active site of chorismate mutase from B. subtilus. These included primary 13C and 18O and secondary 3H effects for substitutions at the bond-making and bond-breaking positions. The initial structures of the putative stationary points on the potential energy surface, required for the calculations of isotope effects using the CAMVIB/CAMISO programs, have been selected from hybrid QM/MM molecular dynamical simulations using the DYNAMO program. Refinement of the reactant complex and transition-state structures has been carried out by means of AM1/CHARMM24/TIP3P calculations using the GRACE program, with full gradient relaxation of the position of > 5200 atoms for the enzymic simulations, and with a box containing 711 water molecules for the corresponding reaction in aqueous solution. Comparison of these results, and of gas phase calculations, with experimental data has shown that the chemical rearrangement is largely rate-determining for the enzyme mechanism. Inclusion of the chorismate conformational pre-equilibrium step in the modelled kinetic scheme leads to better agreement between recent experimental data and theoretical predictions. These results provide new information on an important enzymatic transformation, and the key factors responsible for the kinetics of its molecular mechanism are clarified. Treatment of the enzyme and/or solvent environment by means of a large and flexible model is absolutely essential for prediction of kinetic isotope effects.
The G-protein coupled receptors (GPCRs) superfamily comprise similar proteins arranged into famil... more The G-protein coupled receptors (GPCRs) superfamily comprise similar proteins arranged into families or classes thus making it one of the largest in the mammalian genome.
In 1997, a collection of twenty personal perspectives from eminent chemists was published in Pure... more In 1997, a collection of twenty personal perspectives from eminent chemists was published in Pure and Applied Chemistry to mark the centenary of physical organic chemistry [1]. This Symposium in Print, entitled Physical Organic Chemistry in the 21st Century (POC21C), was organized by the IUPAC Commission on Physical Organic Chemistry, which was chaired at that time by Tom Tidwell, who contributed a historical prologue in which he suggested Stieglitz’s 1899 proposal of carbocations as reaction intermediates as (unwittingly) having given birth to the discipline. The principal authors were Edward Arnett, Daniel Bellus, Ron Breslow, Fulvio Cacace, Jan Engberts, Marye Anne Fox, Ken Houk, Keith Ingold, Alan Katritzky, Ed Kosower, Meir Lahav, Teruaki Mukaiyama, Oleg Nefedov, George Olah, John Roberts, Jean-Michel Savéant, Helmut Schwarz, Andrew Streitwieser, Frank Westheimer, and Akio Yamamoto. Tidwell noted that, whereas they were not all known as physical organic chemists, yet they had a...
Journal of the Chemical Society, Chemical Communications, 1986
Calculations for [2H1]cyclohexane with a scaled quantum-mechanical 3-21G force field indicate a p... more Calculations for [2H1]cyclohexane with a scaled quantum-mechanical 3-21G force field indicate a preference for equatorial deuterium in accord with experiment but contrary to expectation.
Spectrochimica Acta Part A: Molecular Spectroscopy, 1992
The fundamental IR vibrational modes of trifluoroacetyl fluoride CF3C(O)F and trifluoroacetyl chl... more The fundamental IR vibrational modes of trifluoroacetyl fluoride CF3C(O)F and trifluoroacetyl chloride CF3C(O)CI have been reexamined by ab initio molecular orbital calculations and compared with literature assignments. Several bands of the IR spectrum are reassigned. The Q-branch and integrated absorption cross-sections have been measured for vl, v3, 1,4 and v~l fundamental bands for both pressurized and unpressurized samples on each molecule. The UV absorption spectra of CF3C(O)F and CF3C(O)CI show a structureless continuum with a maximum at 210 nm (Omax = 3.20+0.02 x 10-2°cm 2 molecule-~) and 255 nm (Om~ = 7.66 + 0.26 X 10-2o cm 2 molecule-l), respectively. The nature of the electronic transition giving rise to the UV absorption spectrum for CF3C(O)F and CF3C(O)CI has been examined by ab initio molecular orbital calculations. It is attributed to the/[ IA"~-~tA' electronic transition.
Journal of the Chemical Society, Perkin Transactions 2, 1995
... John Wilkie and Ian H. Williams* School of Chemistry, University of Bath, Bath, UK BA2 7A Y .... more ... John Wilkie and Ian H. Williams* School of Chemistry, University of Bath, Bath, UK BA2 7A Y ... Methoxide-formaldeh yde b*d HF/3-2 1 G 2.662 I .420 139.2 HF/6-3 1 G ... Dih y dr op yridine-for maldeh y de-imidazolium Replacement of ammonium by imidazolium as the proton donor ...
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