John Kendrick obtained a PhD in theoretical chemistry from the University of Manchester. After working in Berlin at the Hahn Meitner Institute and at the EPSRC, Daresbury Laboratories, he joined ICI to work on the application of theory and modelling to industrial problems in catalysis, polymers, energetic materials and dispersants. He is a member of the American Chemical Society and a Fellow of the Royal Society of Chemistry. He is treasurer for the Molecular Modelling Group of the RSC. He has been involved in the development of the GAMESS-UK ab initio molecular orbital package and is director of Computing for Science Ltd, the company which markets the software. He joined the Institute of Pharmaceutical Innovation at the University of Bradford in 2005 and he is a member of the Molecular and Solid State Modelling Group, the Crystal Engineering Cluster and the Computational Group.
Abstract: Two force fields, the GROMOS53A5/53A6 (united atom) and the AMBER95 (all atom) parameter sets, coupled
with partial atomic charges derived from quantum mechanical calculations were evaluated for their ability to
reproduce the known crystalline forms of the polyols mannitol and sorbitol. The force fields were evaluated
using molecular dynamics simulations at 10 K (which is akin to potential energy minimization) with the simulation cell lengths and angles free to evolve. Both force fields performed relatively poorly, not being able to simultaneously reproduce all of the crystal structures within a 5% deviation level. The parameter sets were then systematically optimized using sensitivity analysis, and a revised AMBER95 set was found to reproduce the crystal structures with less than 5% deviation from experiment. The stability of the various crystalline forms for each of the parameter sets (original and revised) was then assessed in extended MD simulations at 298 K and 1 bar covering 1 ns simulation time. The AMBER95 parameter sets (original and revised) were found to be effective in reproducing the crystal structures in these more stringent tests. Remarkably, the performance of the original AMBER95 parameter set was found to be slightly better than that of the revised set in these simulations at 298 K. The results of this study suggest that, whenever feasible, one should include molecular simulations at elevated temperatures when optimizing parameters.
Abstract: Traditionally materials with the fluorite and perovskite structures have dominated the research in the area of oxide ion/proton conducting solid electrolytes. In such cases, the key defects are oxide ion vacancies, and conduction proceeds via a simple vacancy hopping mechanism. In recent years, there has been growing interest in alternative structure types, many of which contain tetrahedral moieties. For these new systems, an understanding of the accommodation of defects and the nature of the conduction mechanism is important for the optimisation of their conductivities, as well as to help target related structures that may display high oxide ion/proton conduction. Computer modelling studies on a range of systems containing tetrahedral moieties are presented, including apatite-type La9.33+xGe6O26+3x/2, cuspidine-type La4Ga2–xTixO9+x/2 and La1–xBa1+xGaO4–x/2. The type of anion defect (vacancy or interstitial), their location and the factors affecting their incorporation are discussed. In addition, modelling data to help to understand their conduction mechanisms are presented, showing novel aspects including the important role of the tetrahedral moieties in the conduction processes.
Abstract: The terahertz frequency spectrum of pentaerythritol tetranitrate (PETN) is calculated using Discover[1] with the COMPASS[2] force field, CASTEP[3] and PWscf.[4] The calculations are compared to each other and to terahertz spectra (0.3-3 THz) of crystalline PETN recorded at 4 K. A number of analysis methods are used to characterise the calculated normal modes.
Abstract: We report on the organization and outcome of the fourth blind test of crystal structure prediction, an international collaborative project organized to evaluate the present state in computational methods of predicting the crystal structures of small organic molecules. There were 14 research groups which took part, using a variety of methods to generate and rank the most likely crystal structures for four target systems: three single-component crystal structures and a 1:1 cocrystal. Participants were challenged to predict the crystal structures of the four systems, given only their molecular diagrams, while the recently determined but as-yet unpublished crystal structures were withheld by an independent referee. Three predictions were allowed for each system. The results demonstrate a dramatic improvement in rates of success over previous blind tests; in total, there were 13 successful predictions and, for each of the four targets, at least two groups correctly predicted the observed crystal structure. The successes include one participating group who correctly predicted all four crystal structures as their first ranked choice, albeit at a considerable computational expense. The results reflect important improvements in modelling methods and suggest that, at least for the small and fairly rigid types of molecules included in this blind test, such calculations can be constructively applied to help understand crystallization and polymorphism of organic molecules.
Abstract: Fluticasone propionate is a synthetic glucocorticoid with potent anti-inflammatory activity that has been used effectively in the treatment of chronic asthma. The present work reports a vibrational spectroscopic study of fluticasone propionate and gives proposed molecular assignments on the basis of ab initio calculations using BLYP density functional theory with a 6-31G* basis set and vibrational frequencies predicted within the quasi-harmonic approximation. Several spectral features and band intensities are explained. This study generated a library of information that can be employed to aid the process monitoring of fluticasone propionate.
Abstract: In the 2007 blind test of crystal structure prediction hosted by the Cambridge Crystallographic Data Centre (CCDC), a hybrid DFT/MM method correctly ranked each of the four experimental structures as having the lowest lattice energy of all the crystal structures predicted for each molecule. The work presented here further validates this hybrid method by optimizing the crystal structures (experimental and submitted) of the first three CCDC blind tests held in 1999, 2001, and 2004. Except for the crystal structures of compound IX, all structures were reminimized and ranked according to their lattice energies. The hybrid method computes the lattice energy of a crystal structure as the sum of the DFT total energy and a van der Waals (dispersion) energy correction. Considering all four blind tests, the crystal structure with the lowest lattice energy corresponds to the experimentally observed structure for 12 out of 14 molecules. Moreover, good geometrical agreement is observed between the structures determined by the hybrid method and those measured experimentally. In comparison with the correct submissions made by the blind test participants, all hybrid optimized crystal structures (apart from compound II) have the smallest calculated root mean squared deviations from the experimentally observed structures. It is predicted that a new polymorph of compound V exists under pressure.
Abstract: The surface energy of a-lactose monohydrate measured by inverse gas chromatography (IGC) is reported along with a dynamic molecular modelling study of the interaction of the various molecular probes with different surfaces of a-lactose monohydrate. The IGC results show that a-lactose monohydrate is acidic in nature. Using quantitative calculations of the energy of adsorption, the acidic nature of the surface is confirmed and the calculated values agree closely with the experimentally measured values. Along with the acidic nature, dynamic molecular modelling also
reveals that the presence of a channel and water molecules on a surface affects the surface energetics of that face. The presence of water on the surface can decrease or increase the surface energy by either blocking or attracting a probe molecule, respectively. This property of water depends on its position and association with other functional groups present on the surface. The effect of a channel or cavity on the surface energy is shown to depend on its size, which determines whether the functional groups in the channel are assessable by probe molecules or not. Overall molecular modelling explains, at the molecular level, the effect of different factors affecting the surface energy of individual faces of the crystal.
Abstract: Salbutamol hemisulphate is a relatively selective beta2-adrenergic agonist and is used as a bronchodilator. In this work, we present a detailed vibrational spectroscopic investigation of salbutamol hemisulphate using mid-infrared and near-infrared Fourier-transform (NIR-FT) Raman spectroscopies. These data are supported by quantum chemical calculations, which allow us to characterise the vibrational spectra of this compound reasonably. As such, this study could be viable for examining the way in which this drug interacts with its target molecules
Abstract: The two known crystalline phases of resorcinol and their phase transitions are of considerable interest. The crystals exhibit pyro- and piezo-electricity and, remarkably, the higher temperature phase is the denser phase. Furthermore, crystals of the phase, by virtue of having a polar axis, have played a crucial role in investigating fundamental issues of crystal growth. We report an optimized force field for the molecular simulation of crystalline phases of resorcinol. The hydroxyl groups of the resorcinol molecule have a torsional degree of freedom and the molecule adopts a different conformation in each of the two phases of resorcinol. The torsional barrier, therefore, was considered to be critical and has been characterized using ab initio methods. Although the atomic partial charges showed some dependence on the molecular conformation, a single set of partial charges was found to be sufficient in describing the electrostatic potential for all conformations. The parameters for the van der Waals interactions were optimized using sensitivity analysis. The proposed force field reproduces not only the static structures but also the stability of the crystalline phases in extended molecular dynamics simulations.
Abstract: The predicted stability differences of the conformational polymorphs of oxalyl dihydrazide and
ortho-acetamidobenzamide are unrealistically large when the modeling of intermolecular energies is solely based on the isolated-molecule charge density, neglecting charge density polarization. Ab initio calculated crystal electron densities showed qualitative differences depending on the spatial arrangement of molecules in the lattice with the greatest variations observed for polymorphs that differ in the extent of inter- and intramolecular hydrogen bonding. We show that accounting for induction dramatically alters the calculated stability order of the polymorphs and reduces their predicted stability differences to be in better agreement with experiment. Given the challenges in modeling conformational polymorphs with marked differences in hydrogen bonding geometries, we performed an extensive periodic density functional study with a range of exchange-correlation functionals using both atomic and plane wave basis sets. Although such electronic structure methods model the electrostatic and polarization contributions well, the underestimation of dispersion interactions by current exchange-correlation functionals limits their applicability. The use of an
empirical dispersion-corrected density functional method consistently reduces the structural
deviations between the experimental and energy minimized crystal structures and achieves plausible stability differences. Thus, we have established which types of models may give worthwhile relative energies for crystal structures and other condensed phases of flexible molecules with intra- and intermolecular hydrogen bonding capabilities, advancing the possibility of simulation studies on polymorphic pharmaceuticals.
Abstract: The separation of racemates into pure enantiomers through crystallization is an important industrial process. This study provides further validation of a novel, predictive approach for spontaneous resolution in which crystal structure prediction simulations are used to explore the relative stabilities of racemic solids versus enantiopure solids. 2-(4-Hydroxyphenyl)-2,5,5-trimethylpyrrolidine-1-oxy (compound 1) has previously been shown to be a racemic conglomerate, while a similar compound, 2-(3-hydroxyphenyl)-2,5,5-trimethylpyrrolidine-1-oxy (compound 2), was not. A conformational search using the Dreiding force field revealed 10 conformational minima for compound 1, and 20 for compound 2. Atomic charges were calculated using unrestricted DFT B3LYP 6-311G** optimized structures, and a crystal structure prediction was performed using the Dreiding force field, considering all low-energy gas-phase conformations and all relevant space groups. Analysis of the predicted crystal structures suggests that compound 1 is a racemic conglomerate, but compound 2 is not. This is in agreement with the experimental evidence.
Abstract: A molecular mechanics conformational analysis was performed on the ionic form of ephedrine using the Dreiding, CVFF and CFF force fields. These calculations were then refined using semi-empirical and ab initio quantum mechanical methods. The results were compared to experimental X-ray data collected in the Cambridge Structural Database (CSD) and to NMR coupling constants. The findings showed that the experimentally accessible conformations are local minima of the isolated molecule rather than the global minimum, access to which is inhibited by an energy barrier for rotation around the OCCN torsion. There is an intra-molecular hydrogen bond between the N+H and OH groups, which dominates the low-energy conformations. The different methods produced similar results but, after comparison with the CSD and NMR information, the ab initio methods are shown to be better at predicting the conformations found by experiment. (C) 2007 Elsevier B.V. All rights reserved.
Abstract: The need for greater energy efficiency has garnered increasing support for the use of fuel-cell technology, a prime example being the solid-oxide fuel cell1, 2. A crucial requirement for such devices is a good ionic (O2- or H+) conductor as the electrolyte3, 4. Traditionally, fluorite- and perovskite-type oxides have been targeted3, 4, 5, 6, although there is growing interest in alternative structure types for intermediate-temperature (400–700 °C) solid-oxide fuel cells. In particular, structures containing tetrahedral moieties, such as La1-xCaxMO4-x/2(M=Ta,Nb,P) (refs 7,8), La1-xBa1+xGaO4-x/2 (refs 9,10) and La9.33+xSi6O26+3x/2 (ref. 11), have been attracting considerable attention recently. However, an atomic-scale understanding of the conduction mechanisms in these systems is still lacking; such mechanistic detail is important for developing strategies for optimizing the conductivity, as well as identifying next-generation materials. In this context, we report a combined experimental and computational modelling study of the La1-xBa1+xGaO4-x/2 system, which exhibits both proton and oxide-ion conduction9, 10. Here we show that oxide-ion conduction proceeds via a cooperative 'cog-wheel'-type process involving the breaking and re-forming of Ga2O7 units, whereas the rate-limiting step for proton conduction is intra-tetrahedron proton transfer. Both mechanisms are unusual for ceramic oxide materials, and similar cooperative processes may be important in related systems containing tetrahedral moieties.
Abstract: In this paper, molecular modelling was used to investigate the nature of probe/surface interactions during the analysis of Dβ-mannitol using inverse gas chromatography (IGC). IGC was used to experimentally measure the dispersive components of surface free energy () and the specific components of free energy of adsorption () of Dβ-mannitol by calculating the retention time of non-polar (n-alkanes) and polar (tetrahydrofuran and chloroform) probes, respectively. The results showed that Dβ-mannitol surface is acidic in nature because the basic probe had more interaction with the surface as compared to acidic probe. Cerius2 software package was used to model the two morphologically important surfaces, which showed the presence of surface hydroxyl groups. Molecular dynamics simulations were performed in Cerius2 to model the adsorption of the same probes (n-alkanes, tetrahydrofuran and chloroform) on the Dβ-mannitol surfaces. The adsorption energies calculated from the simulation showed a close match to those determined experimentally. The calculated values are slightly higher for all probes except chloroform, but as a single perfect crystal was modelled without considering the effect of impurities, solvent and other physical factors this is not unexpected.
Abstract: Martensitic transformations are of considerable technological importance, a particularly promising application being the possibility of using martensitic materials, possibly proteins, as tiny machines. For organic crystals, however, a molecular level understanding of such transformations is lacking. We have studied a martensitic-type transformation in crystals of the amino acid DL-norleucine using molecular dynamics simulation. The crystal structures of DL-norleucine comprise stacks of bilayers (formed as a result of strong hydrogen bonding) that translate relative to each other on transformation. The simulations reveal that the transformation occurs by concerted molecular displacements involving entire bilayers rather than on a molecule-by-molecule basis. These observations can be rationalized on the basis that at sufficiently high excess temperatures, the free energy barriers to concerted molecular displacements can be overcome by the available thermal energy. Furthermore, in displacive transformations, the molecular displacements can occur by the propagation of a displacement wave (akin to a kink in a carpet), which requires the molecules to overcome only a local barrier. Concerted molecular displacements are therefore considered to be a significant feature of all displacive transformations. This finding is expected to be of value toward developing strategies for controlling or modulating martensitic-type transformations.
Abstract: Crystal structure prediction simulations are reported on 5-hydroxymethyl-2-oxazolidinone and 4-hydroxymethyl-2-oxazolidinone to establish the feasibility of predicting the spontaneous resolution of racemates of small organic molecules. It is assumed that spontaneous resolution occurs when the enantiomorph is more stable than the racemic solid. The starting point is a gas phase conformational search to locate all low-energy conformations. These conformations are used to predict the possible crystal structures of 5- and 4-hydroxymethyl-2-oxazolidinone. In both cases, the racemic crystal structure is predicted to have the lowest energy. The energy differences between the lowest-energy racemic solids and the lowest-energy enantiomorphs are 0.2 kcal mol(-1) for 5-hydroxymethyl-2-oxazolidinone and 0.9 kcal mol(-1) for 4-hydroxymethyl-2-oxazolidinone. In the case of 4-hydroxymethyl-2-oxazolidinone, where the racemic crystal is known to be more stable and the experimental crystal structures of both the racemate and the enantiomorph are available, the simulation results match the observed data. For 5-hydroxymethyl-2-oxazolidinone, where only enantiopure crystals are observed experimentally, the known experimental structure is found 1.6 kcal mol(-1) above the lowest-energy predicted structure. This work shows that it is possible to predict whether the racemate of a small chiral molecule can be resolved spontaneously, although further advances in the accuracy of lattice energy calculations are required.
Abstract: The Raman spectrum of budesonide is reported for the first time, and molecular assignments are proposed on the basis of ab initio BLYP DFT calculations with a 6-31 G* basis set and vibrational wavenumbers predicted on a quasi-harmonic approximation. Comparison with previously published infrared data has explained several spectral features, and the relative band intensities in the C=O and C=C stretching regions are interpreted. The results from this study provide data that can be used for the preparative process monitoring of budesonide, an important steroidal pharmaceutical in various dosage forms, and its interaction with excipients and other components. Copyright (C) 2007 John Wiley & Sons, Ltd.
Abstract: A description of the ab initio quantum chemistry package GAMESS-UK is presented. The package offers a wide range of quantum mechanical wavefunctions, capable of treating systems ranging from closed-shell molecules through to the species involved in complex reaction mechanisms. The availability of a wide variety of correlation methods provides the necessary functionality to tackle a number of chemically important tasks, ranging from geometry optimization and transition-state location to the treatment of solvation effects and the prediction of excited state spectra. With the availability of relativistic ECPs and the development of ZORA, such calculations may be performed on the entire Periodic Table, including the lanthanides. Emphasis is given to the DFT module, which has been extensively developed in recent years, and a number of other, novel features of the program. The parallelization strategy used in the program is outlined, and detailed speedup results are given. Applications of the code in the areas of enzyme and zeolite catalysis and in spectroscopy are described.
Abstract: We describe the work of the European project QUASI (Quantum Simulation in Industry, project EP25047) which has sought to develop a flexible QM/MM scheme and to apply it to a range of industrial problems. A number of QM/MM approaches were implemented within the computational chemistry scripting system, ChemShell, which provides the framework for deploying a variety of independent program packages. This software was applied in several large-scale QM/MM studies which addressed the catalytic decomposition of N2O by Cu-containing zeolites, the methanol synthesis reaction catalysed by Cu clusters supported on ZnO surfaces, and the modelling of enzyme structure and reactivity. (C) 2003 Elsevier B.V. All rights reserved.
Abstract: There is a need for novel energetic materials that are able to meet the challenging requirements that will be placed on the next generation of formulations. This will undoubtedly include the synthesis and development of new and existing formulation components; crystalline explosives, energetic binders, energetic plasticisers, bonding agents and other processing aids. Usually performance is the main driver but reduced vulnerability, high quality, improved mechanical properties and ease of disposal are ever increasing in importance. As part of the life cycle of an explosive system, molecular modelling has played a key part in the ICI/DRA collaboration actively pursuing the initial design phase in the U.K. Molecular modelling techniques commonly used to tackle industrial problems have been manipulated and developed to investigate problems covering the whole development pathway for novel energetic materials. Examples of the impact of molecular modelling on the development of novel energetic materials will be described. The development of a molecular model for the description of the III and IV phases of ammonium nitrate will be used to illustrate the concepts. (C) 1997 Elsevier Science Ltd. All rights reserved.
Abstract: Ab initio calculations on fragments of polyether ketone polymers are used to determine both inter- and intra-molecular forces in these systems. The results indicate that, even for these conjugated systems, it is possible to choose relatively small fragments which are representative of the complete system. The information generated is used to calculate the crystal structure of several poly(aryl-ether-ketone)s, including poly(phenylene oxide), PEK, PEKK and PEEK. The calculated perfect structures are in good agreement with experimental information from X-ray crystallography. Experimental trends in the a-, b- and c-lattice parameters, observed as the ketone content of the polymer is altered, are also reproduced. Metastable crystal structures for several of the polymers are predicted, which are very close to a new crystal structure proposed recently for PEKK.
Abstract: Ab initio molecular orbital calculations are reported on the energetics for torsional motion of N-phenyl phthalimide using 3-21G, 6-31G, and 6-31G** basis sets and incorporating electron correlation effects for selected geometries. With the largest basis set, a minimum energy is found for a torsion angle of 59.2-degrees. Atomic charges are assigned to the molecules on the basis of a least-squares fit to the molecular electrostatic potential. This information is then used in molecular mechanics calculations of the crystal structure, where the calculated unit cell parameters are in good agreement with those observed experimentally.
Abstract: High resolution C1s spectra are reported for polyethylene, polypropylene, hexatriacontane (n-C36H74) and polystyrene. Asymmetry is observed on the high binding energy side of the lineshape for the first three of these compounds, and is attributed to the excitation of C-H stretching vibrations during core level photoionization. The effect only becomes apparent for experimental linewidths < 1.0 eV. Linewidths reported here are typically < 0.85 eV. For polystyrene a much smaller degree of asymmetry is observed.
Abstract: The crystal and molecular structures of two isomeric, aromatic, pyromellitimide oligomers 1 and 2 have been determined by single-crystal X-ray diffraction. Crystal data for 1 (C46H28N2O10S2): triclinic, P1BAR; a = 8.038 (3), b = 10.947 (3), c = 11.308 (4) angstrom; alpha = 95.75 (3), beta = 105.79 (2), gamma = 92.89 (3)-degrees. Crystal data for 2 (C46H28N2O10S2): monoclinic, P2(1)/a; a = 11.844 (5), b = 6.977 (2), c = 22.694 (6) angstrom; beta = 101.96 (3)-degrees. The structure of the yellow isomer (2) provides the first direct evidence of complementary, face-to-face stacking between electron-rich imidophenoxy (N-Ar-O) and electron-poor pyromellitimide units in adjacent chains, an association long suspected but not yet conclusively demonstrated in aromatic polyimides. In contrast, the colorless oligomer (1) adopts a packing mode in which all the parallel ring-ring contacts occur between aromatic systems of like, rather than complementary, electronic character.
Abstract: A general methodology is developed for incorporating accurate electrostatic information from ab initio molecular orbital calculations into molecular mechanics calculations. Examples are given of the method applied to simple aromatic organic molecules. A program has been developed for displaying the results of the ab initio calculations on a Silicon Graphics workstation. The technique developed here provides an alternative method for including electrostatic interactions in molecular mechanics calculations and is compared with other methods for determining atomic changes.
Abstract: The calculation of the energetics of torsional motion in a number of aromatic, diphenyl molecules using the ab initio SCF method is described. The molecules chosen represent linkages, such as ether, ketone, sulphide, sulphone, methylene an biphenyl, which are found in many aromatic polymers. The results of the calculations should provide a useful 'benchmark' for attempts at using molecular mechanics methods to study the motion of the polymer chain. Where details are available, the calculated torsional and geometric parameters are in good agreement with experiment.
