Grid service orchestration using the Business Process Execution Language (BPEL)

Modern scientific applications often need to be distributed across grids. Increasingly applications rely on services, such as job submission, data transfer or data portal services. We refer to such services as grid services. While the invocation of grid services could be hard coded in theory, scientific users want to orchestrate service invocations more flexibly. In enterprise applications, the orchestration of web services is achieved using emerging orchestration standards, most notably the Business Process Execution Language (BPEL). We describe our experience in orchestrating scientific workflows using BPEL. We have gained this experience during an extensive case study that orchestrates grid services for the automation of a polymorph prediction application

Modelling of crystal structure of cis-1,2,3,6 and 3,4,5,6-tetrahydrophthalic anhydrides using lattice energy calculations

Lattice energy calculations using a model potential were performed to model the crystal structures of cis-1,2,3,6- and 3,4,5,6-tetrahydrophthalic (THP) anhydrides. The optimized molecular models using the DFT method at the B3LYP/6-31G** level were found consistent with the available experimental evidence and allowed all differences observed in crystal packing between cis-1,2,3,6- and 3,4,5,6-THP anhydrides to be reproduced. Calculations provide evidence for the presence of dipole–dipole C=O?C=O intermolecular interactions and support the idea that the molecules distort from their ideal geometries, improving packing in both crystals. The search for minima in the lattice energy of both crystals amongst the more common space groups with Z’?=?1, using a simulated annealing crystal structure prediction procedure followed by lattice energy minimization showed that the observed structure of 3,4,5,6-THP anhydride (Z’?=?2) is the thermodynamically most stable, and allowed us to justify why 3,4,5,6-THP anhydride crystallizes in such a complex structure with 16 molecules in the unit cell. The computational model was successful in predicting the second observed form at 173 K for cis-1,2,3,6-THP anhydride as a polymorph, and could predict several hypothetical structures with Z’?=?1 that appear competitive with the observed structures. The results of phonon estimates of zero point intermolecular vibrational energy and entropy suggest that crystal structures of cis-1,2,3,6-THP anhydride cannot be predicted solely on the basis of lattice energy; factors other than thermodynamics favor the observed structures

Computational prediction of organic crystal structures

Crystal Structure Prediction (CSP) is used by the pharmaceutical industry to assess whether other polymorphs of active pharmaceutical ingredients (API) might cause problems during manufacturing processes. In the 7th Blind Test of CSP, organized by the Cambridge Crystallographic Data Centre (CCDC), one of the targets (XXX) was to predict the possible stoichiometries of two co−crystals of cannabinol (CBN) and tetramethylpyrazine (TMP). This thesis describes the methodology used for the submission of predicted structures of these co−crystals, concluding that the likely stoichiometries were 1CBN:1TMP and 1CBN:2TMP, as these were more stable than the component structures and had plausible crystal packings. Following submission, this thesis analysed the crystal structures of TMP and have proposed starting points for the crystal structure refinement of a structure (MPYRAZ03) on the Cambridge Structural Database (CSD) that has no atomic coordinates. The CBN search failed to find the Z’=2 experimental crystal structure (CANNOL) that is on the CSD, which has a high energy molecular conformation. This failure was found to be due to the limits on the structure generation program (Sobol sequence and density setting) and was exacerbated by the point charge model failing to model the CANNOL hydrogen bonding adequately. Alternative strategies to find the experimental structure were proposed, but they were deemed too expensive to run a full search. As this thesis was being completed, experimental co−crystal structures were provided by CCDC. After comparing with experimental structures, there was no experimental co−crystal structure in co−crystal CSP searches used in this thesis. This problem was caused by the folded pentane tail instead of the hydroxyl group

The induction contribution to the lattice energy of organic crystals

A recently developed method for generating distributed, localized atomic polarizabilities from the ab initio molecular charge density is used to assess the importance of the induction energy in crystal structures of small organic molecules. Two models are first contrasted based on large cluster representing the crystalline environment: one using the polarizability model in which induced multipoles are evaluated in response to the electrostatic field due to atomic multipoles; the other is a complementary procedure in which the same cluster is represented by atomic point-charges and the molecular charge density is calculated ab initio in this environment. The comparable results of these two methods show that the contribution to the lattice energy from the induction term can differ significantly between polymorphic forms, for a selection of organic crystal structures including carbamazepine and oxalyl dihydrazide, and 3-azabicyclo[3,3,1]nonane-2,4-dione. The observed charge density polarization of naphthalene in the crystalline state is also reproduced. This demonstrates that explicit inclusion of the induction energy, rather than its absorption into an empirically fitted repulsion-dispersion potential, will improve the relative ordering of the lattice energies for computed structures, and that it needs to be included in crystal structure prediction. Hence, the distributed atomic polarizability model was coded into the lattice-energy minimization program DMACRYS (which was developed as a Fortran90 recoding of DMAREL) to allow the induction energy to be calculated

A theoretical study of metal-organic frameworks

Among the options for carbon sequestration, the development of CO2 capture materials has gained momentum over the past two decades. The design and construction of chemical and physical absorbents for the capture of CO2 and clean energy storage are a crucial technology for a sustainable low-carbon future. Metal-organic frameworks (MOFs) provide a new vision for the adsorption of molecules on solid surfaces. The interest in MOFs is owed to their ultrahigh porosity, high surface areas and tuneable pore sizes and shapes. The main objective of this thesis was to adopt a rational predictive capacity used in MOF design to control properties such as framework porosity and flexibility on a molecular scale. The in-silico studies were carried out by using ab initio quantum mechanical approaches such as density functional theory and perturbation theory. In addition, semi-classical methods like the Grand Canonical Monte Carlo (GCMC) approach was also used. A structural motif called vicinal fluorination was adopted to study MOF linkers in isolation and in a framework. An extensive conformational study, in various solvents, was carried out to investigate the effect of vicinal fluorination on the isolated MOF linkers and therefore elucidate their conformational stability. The effect of fluorination on adsorption isotherms was also investigated. Moreover, various fluorination patterns were explored. Adsorption isotherms of a non-fluorinated copperbased MOF based on experimental work, and its various fluorinated analogues were predicted using the GCMC method. It was found that vicinal fluorination is not dominant in controlling conformations of some MOF linkers. Rather, an interplay of interactions, including solute and steric interactions, influence the conformational stability on rotational profiles. However, vicinal fluorination was shown to control the flexibility of the linkers used in MOFs as it controls the force constants around the minima of rotational profiles of isolated MOF linkers. The study also highlighted the importance of the solvent on the relative energies of the linker conformations – this has a potential impact on the synthesis of MOFs. With the help of computational methods and validation from experimental data, the structural and sorption properties of the framework, upon fluorination, were shown to have consequences on the adsorption properties of the MOF. Vicinally fluorinated frameworks were shown to have higher uptakes at a low temperature and low pressures

Non-empirical Force-Field Development for Weakly-Bound Organic Molecules

This thesis pioneers the development of non-empirical anisotropic atom-atom force-fields for organic molecules, and their use as state-of-the-art intermolecular potentials for modelling the solid-state. The long-range electrostatic, polarization and dispersion terms have been derived directly from the molecular charge density, while the short-range terms are obtained through fitting to the symmetry-adapted perturbation theory (SAPT(DFT)) intermolecular interaction energies of a large number of different dimer configurations. This study aims to establish how far this approach, previously used for small molecules, could be applied to specialty molecules, and whether these potentials improve on the current empirical force-fields FIT and WILLIAMS01. The scaling of the underlying electronic structure calculations with system size means many adaptions have been made. This project aims to generate force-fields suitable for use in Crystal Structure Prediction (CSP) and for modelling possible polymorphs, particularly high-pressure polymorphs. By accurately modelling the repulsive wall of the potential energy surface, the high pressure/temperature conditions typically sampled by explosive materials could be studied reliably, as shown in a CSP study of pyridine using a non-empirical potential. This thesis also investigates the transferability of these potentials from the gas to condensed-phase, as well as the transferability and importance of the intermolecular interactions of flexible functional groups, in particular NO2 groups. The charge distribution was found to be strongly influenced by variations in the observed NO2 torsion angle and the conformation of the rest of the molecule. This conformation dependence coupled with the novelty of the methods and size of the molecules has made developing non-empirical models for flexible nitro-energetic materials very challenging. The thesis culminates in the development of a bespoke non-empirical force-field for rigid trinitrobenzene and its use in a CSP study

Towards more efficient screening of pharmaceutical cocrystals

Pharmaceutical cocrystals are formed between active pharmaceutical ingredients (APIs) and coformers that are biologically safe. Cocrystals are of considerable relevance to the pharmaceutical industry as they offer the ability of optimizing the physical properties of an API whilst retaining its biological function. However, producing cocrystals is experimentally challenging and often results in undesired forms. The objective of work presented herein is to investigate a more effective screening approach. Assuming that the formation of cocrystals is thermodynamically driven, we tested whether a contemporary computational methodology can account for the formation of 26 known cocrystals. By comparing their calculated lattice energies with the sum of their components we found the majority of cocrystals to be thermodynamically more stable, implying that this computational method is sufficient and could be applied to the prediction of cocrystal formation. An experimental screening procedure for the formation of succinic acid and 4-aminobenzoic acid cocrystals was explored. Grinding and hot stage microscopy experiments provided a rapid indication of cocrystal formation. For systems showing an indication of cocrystal formation, more extensive screening was carried out using slow solvent evaporation with a diverse variety of solvents to grow single crystals for X-ray structural determination. The results produced 4 novel cocrystals. Finally a multistage computational process was used to generate lattice energy landscapes for succinic acid•2,2´-bipyridine and succinic acid•1,4-dicyanobenzene cocrystals and their components. Analysis of these landscapes rationalized why only one of these cocrystals had been formed in the experimental screening. This thesis shows that computational methods can be used as a complementary technique to experimental screening of cocrystals. The calculations could have been performed prior to the experimental work and so have the potential to narrow down experimental investigations to the most promising candidates

Polymorphism within the fenamate family: the consequences of chloro-methyl replacement

Both mefenamic acid (MA) and tolfenamic acid (TA) are polymorphic with three and five forms respectively. MA and TA are structurally similar molecules that differ in the replacement of a methyl on MA with a chloro group on TA. This thesis uses a joint computational and experimental approach to investigate the polymorphism of MA and TA and explores differences in the packings upon chloro-methyl replacement. To compliment an earlier crystal structure prediction (CSP) study on TA, the crystal energy landscape of MA was computed. Analysis showed there were a number of predicted structures that were competitive in energy with the known forms of MA. Isostructural relationships between MA and TA that were identified from the observed polymorphs and the predicted forms from the CSP studies were investigated in a range of templating experiments. The isostructural, not isomorphous, relationship between MA I and TA IV was explored and a solid solution series, isomorphous with MA form I, was obtained from ethanol and characterised by low temperature single crystal X-ray diffraction (SCXRD). Seeding an ethanol solution of TA with MA form I seeds nucleated a new polymorph of TA (VI) that was characterised by SCXRD and was isomorphous with MA form I. A second new form of TA (VII) was discovered, and identified by powder X-ray diffraction, when exploring the sublimation of TA onto a copper surface. Thermal analysis showed that TA VII transformed to TA I upon heating. Using a similar sublimation procedure, it was observed that if MA was sublimed onto copper, form I was obtained, yet if MA was sublimed onto glass, form II was obtained. The CSP methodology was tested by participation in the CCDC blind test and was successful in predicting the observed crystal structure of the cocrystal XXV as the global minimum