No / A hybrid molecular mechanics and quantum mechanics solid state DFT method is used to re-rank the stability of racemic and enantiopure crystal structures of four molecules; 4-hydroxymethyl-2-oxazolidinone, 5-hydroxymethyl-2-oxazolidinone, 2-(4-hydroxyphenyl)-2,5,5-trimethylpyrrolidine-1-oxy and 2-(3-hydroxyphenyl)-2,5,5-trimethylpyrrolidine-1-oxy. Previous work using a force field based method to predict these crystal structures indicated that the lattice energy may be a suitable criterion for predicting whether a chiral molecule will resolve spontaneously on crystallisation. However, in some cases, the method had predicted an unrealistically high lattice energy for the structure corresponding to the experimentally observed one. The Hybrid DFT method successfully predicts those molecules which resolve spontaneously and furthermore predicts satisfactory lattice energies for all experimentally observed structures. Based on a comparison of the predicted lattice energies from the two methods it is concluded that the force fields used were not sufficiently accurate to predict spontaneous resolution with any confidence. However, the Hybrid DFT method is shown to be sufficiently accurate for making such predictions.

Yes / Mandelic acids are prototypic chiral molecules where the sensitivity of crystallized forms (enantiopure/racemic compound/polymorphs) to both conditions and substituents provides a new insight into the factors that may allow chiral separation by crystallization. The determination of a significant number of single crystal structures allows the analysis of 13 enantiopure and 30 racemic crystal structures of 21 (F/Cl/Br/CH3/CH3O) substituted mandelic acid derivatives. There are some common phenyl packing motifs between some groups of racemic and enantiopure structures, although they show very different hydrogen-bonding motifs. The computed crystal energy landscape of 3-chloromandelic acid, which has at least two enantiopure and three racemic crystal polymorphs, reveals that there are many more possible structures, some of which are predicted to be thermodynamically more favorable as well as slightly denser than the known forms. Simulations of mandelic acid dimers in isolation, water, and toluene do not differentiate between racemic and enantiopure dimers and also suggest that the phenyl ring interactions play a major role in the crystallization mechanism. The observed crystallization behavior of mandelic acids does not correspond to any simple “crystal engineering rules” as there is a range of thermodynamically feasible structures with no distinction between the enantiopure and racemic forms. Nucleation and crystallization appear to be determined by the kinetics of crystal growth with a statistical bias, but the diversity of the mandelic acid crystallization behavior demonstrates that the factors that influence the kinetics of crystal nucleation and growth are not yet adequately understood. / EPSRC, Max Planck Society for the Advancement of Sciences, UCL-MPS Impact Ph.D. Fellowship, EU COST Action

The physical and chemical properties of materials are intimately related to their underlying crystal structure: the detailed arrangement of atoms and chemical bonds within. This thesis uses computational methods to predict crystal structure, with a particular focus on structures and stable phases that emerge at high pressure. We explore three distinct systems. We first apply the ab initio random structure searching (AIRSS) technique and density functional theory (DFT) calculations to investigate the high-pressure behaviour of beryllium, magnesium and calcium difluorides. We find that beryllium fluoride is extensively polymorphic at low pressures, and predict two new phases for this compound - the silica moganite and CaCl$_2$ structures - to be stable over the wide pressure range 12-57 GPa. For magnesium fluoride, our results show that the orthorhombic `O-I' TiO$_2$ structure ($Pbca$, $Z=8$) is stable for this compound between 40 and 44 GPa. Our searches find no new phases at the static-lattice level for calcium difluoride between 0 and 70 GPa; however, a phase with $P\overline{6}2m$ symmetry is energetically close to stability over this pressure range, and our calculations predict that this phase is stabilised at high temperature. The $P\overline{6}2m$ structure exhibits an unstable phonon mode at large volumes which may signal a transition to a superionic state at high temperatures. The Group-II difluorides are isoelectronic to a number of other AB$_2$-type compounds such as SiO$_2$ and TiO$_2$, and we discuss our results in light of these similarities. Compressed hydrogen sulfide (H$_2$S) has recently attracted experimental and theoretical interest due to the observation of high-temperature superconductivity in this compound ($T_c$ = 203 K) at high pressure (155 GPa). We use the AIRSS technique and DFT calculations to determine the stable phases and chemical stoichiometries formed in the hydrogen-sulfur system as a function of pressure. We find that this system supports numerous stable compounds: H$_3$S, H$_7$S$_3$, H$_2$S, H$_3$S$_2$, H$_4$S$_3$, H$_2$S$_3$ and HS$_2$, at various pressures. Working as part of a collaboration, our predicted H$_3$S and H$_4$S$_3$ structures are shown to be consistent with XRD data for this system, with H$_4$S$_3$ identified as a major decomposition product of H$_2$S in the lead-up to the superconducting state. Calcium and oxygen are two elements of generally high terrestrial and cosmic abundance, and we explore structures of calcium peroxide (CaO$_2$) in the pressure range 0-200 GPa. Stable structures for CaO$_2$ with $C2/c$, $I4/mcm$ and $P2_1/c$ symmetries emerge at pressures below 40 GPa, which we find are thermodynamically stable against decomposition into CaO and O$_2$. The stability of CaO$_2$ with respect to decomposition increases with pressure, with peak stability occurring at the CaO B1-B2 phase transition at 65 GPa. Phonon calculations using the quasiharmonic approximation show that CaO$_2$ is a stable oxide of calcium at mantle temperatures and pressures, highlighting a possible role for CaO$_2$ in planetary geochemistry, as a mineral redox buffer. We sketch the phase diagram for CaO$_2$, and find at least five new stable phases in the pressure/temperature ranges 0 $\leq P\leq$ 60 GPa, 0 $\leq T\leq$ 600 K, including two new candidates for the zero-pressure ground state structure.

no / 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.

no / 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.

Yes / The sixth blind test of organic crystal-structure prediction (CSP) methods has been held, with five target systems: a small nearly rigid molecule, a polymorphic former drug candidate, a chloride salt hydrate, a co-crystal, and a bulky exible molecule. This blind test has seen substantial growth in the number of submissions, with the broad range of prediction methods giving a unique insight into the state of the art in the field. Significant progress has been seen in treating flexible molecules, usage of hierarchical approaches to ranking structures, the application of density-functional approximations, and the establishment of new workflows and best practices for performing CSP calculations. All of the targets, apart from a single potentially disordered Z0 = 2 polymorph of the drug candidate, were predicted by at least one submission. Despite many remaining challenges, it is clear that CSP methods are becoming more applicable to a wider range of real systems, including salts, hydrates and larger flexible molecules. The results also highlight the potential for CSP calculations to complement and augment experimental studies of organic solid forms. / EPSRC (grants EP/J01110X/1 and EP/K018132/1) and the European Research Council under the European Union’s Seventh Framework Programme (FP/2007-2013)/ERC through grant agreements n. 307358 (ERC-stG- 2012-ANGLE) and n. 321156 (ERC-AG-PE5-ROBOT). The Russian Foundation (14-03-01091). GlaxoSmithKline, Merck, and Vertex. VIDI Research Program 700.10.427, which is financed by The Netherlands Organisation for Scientific Research (NWO), and the European Research Council (ERC-2010-StG, grant agreement n. 259510-KISMOL). Foundation for Fundamental Research on Matter (FOM). NSF grant number ACI-1053575. University of Buenos Aires and the Argentinian Research Council. Conflex Corp. and Ministry of Education, Culture, Sports, Science and Technology. Louisiana Board of Regents Award # LEQSF(2014-17)-RD-A-10 “Toward Crystal Engineering from First Principles”, the NSF award # EPS-1003897 “The Louisiana Alliance for Simulation-Guided Materials Applications (LA-SiGMA)”, and by the Tulane Committee on Research Summer Fellowship. Solar Technologies Go Hybrid initiative of the State of Bavaria, Germany. U.S. Department of Energy under contract DE-AC02-06CH11357. EPSRC (EP/J003840/1, EP/J014958/1) and [EP/J017639/1]. Leadership Fellowship Grant [EP/K013688/1]. Robinson College, Cambridge, and the Cambridge Philosophical Society for a Henslow Research Fellowship. Army Research Office under Grant W911NF-13-1- 0387 and by the National Science Foundation Grant CHE-1152899. Polish National Science Centre Grant No. DEC-2012/05/B/ST4/00086. EPSRC, though grant ESPRC EP/K039229/1, and Eli Lilly. The PhD students support: RKH by a joint UCL Max-Planck Society Magdeburg Impact studentship, REW by a UCL Impact studentship; LI by the Cambridge Crystallographic Data Centre and the M3S Centre for Doctoral Training (EPSRC EP/G036675/1). Army Research Office Grant W911NF-13-1-0387 and by the National Science Foundation Grant CHE-1152899. U.S. Army Research Laboratory and the U.S. Army Research Office under contract/grant number W911NF-13-1-0387 (MET and LV) and MRSEC program of the National Science Foundation under Award Number DMR-1420073 (MET and ES). U.S. Army Research Laboratory and the U.S. Army Research Office contract/grant number W911NF-13-1- 0387 and by the National Science Foundation Grant CHE-1152899. National Science Foundation (DMR-1231586), the Government of Russian Federation (Grant No. 14.A12.31.0003), the Foreign Talents Introduction and Academic Exchange Program (No. B08040) and the Russian Science Foundation, project no. 14-43-00052, base organization Photochemistry Center of the Russian Academy of Sciences. Army Research Office Grant W911NF-13-1-0387 and the National Science Foundation Grant CHE-1152899. Deutsche Forschungsgemeinschaft program DFG-SPP 1807. Department of Energy (DOE) Grant Nos. DE-SC0008626. Office of Science of the U.S. Department of Energy Contract No. DE-AC02-06CH11357. Office of Science of the U.S. Department of Energy contract No. DEAC02-05CH11231.

The main topic of this thesis is the development of computational search methods that are useful in drug design applications. The emphasis is on exhaustiveness of the search method such that it can guarantee a certain level of geometric accuracy. In particular, the following two problems are addressed: (i) Prediction of binding mode of a drug molecule to a receptor and (ii) prediction of crystal structures of drug molecules. Predicting the binding mode(s) of a drug molecule to a target receptor is pivotal in structure-based rational drug design. In contrast to most approaches to solve this problem, the idea in this work is to analyze the search problem from a computational perspective. By building on top of an existing docking tool, new methods are proposed and relevant computational results are proven. These methods and results are applicable for other place-and-join frameworks as well. A fast approximation scheme for the docking of rigid fragments is described that guarantees certain geometric approximation factors. It is also demonstrated that this can be translated into an energy approximation for simple scoring functions. A polynomial time algorithm is developed for the matching phase of the docked rigid fragments. It is demonstrated that the generic matching problem is NP-hard. At the same time the optimality of the proposed algorithm is proven under certain scoring function conditions. The matching results are also applicable for some of the fragment-based de novo design methods. On the practical side, the proposed method is tested on 829 complexes from the PDB. The results show that the closest predicted pose to the native structure has the average RMS deviation of 1.06 °A. The prediction of crystal structures of small organic molecules has significantly improved over the last two decades. Most of the new developments, since the first blind test held in 1999, have occurred in the lattice energy estimation subproblem. In this work, a new efficient systematic search method that avoids random moves is proposed. It systematically searches through the space of possible crystal structures and conducts search space cuts based on statistics collected from the structural databases. It is demonstrated that the fast search method for rigid molecules can be extended to include flexible molecules as well. Also, the results of some prediction experiments are provided showing that in most cases the systematic search generates a structure with less than 1.0°A RMSD from the experimental crystal structure. The scoring function that has been developed for these experiments is described briefly. It is also demonstrated that with a more accurate lattice energy estimation function, better results can be achieved with the proposed robust search method.

The main topic of this thesis is the development of computational search methods that are useful in drug design applications. The emphasis is on exhaustiveness of the search method such that it can guarantee a certain level of geometric accuracy. In particular, the following two problems are addressed: (i) Prediction of binding mode of a drug molecule to a receptor and (ii) prediction of crystal structures of drug molecules. Predicting the binding mode(s) of a drug molecule to a target receptor is pivotal in structure-based rational drug design. In contrast to most approaches to solve this problem, the idea in this work is to analyze the search problem from a computational perspective. By building on top of an existing docking tool, new methods are proposed and relevant computational results are proven. These methods and results are applicable for other place-and-join frameworks as well. A fast approximation scheme for the docking of rigid fragments is described that guarantees certain geometric approximation factors. It is also demonstrated that this can be translated into an energy approximation for simple scoring functions. A polynomial time algorithm is developed for the matching phase of the docked rigid fragments. It is demonstrated that the generic matching problem is NP-hard. At the same time the optimality of the proposed algorithm is proven under certain scoring function conditions. The matching results are also applicable for some of the fragment-based de novo design methods. On the practical side, the proposed method is tested on 829 complexes from the PDB. The results show that the closest predicted pose to the native structure has the average RMS deviation of 1.06 °A. The prediction of crystal structures of small organic molecules has significantly improved over the last two decades. Most of the new developments, since the first blind test held in 1999, have occurred in the lattice energy estimation subproblem. In this work, a new efficient systematic search method that avoids random moves is proposed. It systematically searches through the space of possible crystal structures and conducts search space cuts based on statistics collected from the structural databases. It is demonstrated that the fast search method for rigid molecules can be extended to include flexible molecules as well. Also, the results of some prediction experiments are provided showing that in most cases the systematic search generates a structure with less than 1.0°A RMSD from the experimental crystal structure. The scoring function that has been developed for these experiments is described briefly. It is also demonstrated that with a more accurate lattice energy estimation function, better results can be achieved with the proposed robust search method.

京都大学 / 新制・課程博士 / 博士(工学) / 甲第24581号 / 工博第5087号 / 新制||工||1974(附属図書館) / 京都大学大学院工学研究科材料工学専攻 / (主査)教授 田中 功, 教授 安田 秀幸, 教授 中村 裕之 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DFAM

No / A crystal structure prediction (CSP) study of three small, rigid and structurally related organic compounds (differing only in the position and number of methyl groups) is presented. A tailor-made force field (TMFF; a non-transferable force field specific for each molecule) was constructed with the aid of a dispersion-corrected density functional theory method (the hybrid method). Parameters for all energy terms in each TMFF were fitted to reference data generated by the hybrid method. Each force field was then employed during structure generation. The experimentally observed crystal structures of two of the three molecules were found as the most stable crystal packings in the lists of their force-field-optimised structures. A number of the most stable crystal structures were re-optimised with the hybrid method. One experimental crystal structure was still calculated to be the most stable structure, whereas for another compound the experimental structure became the third most stable structure according to the hybrid method. For the third molecule, the experimentally observed polymorph, which was found to be the fourth most stable form using its TMFF, became the second most stable form. Good geometrical agreements were observed between the experimental structures and those calculated by both methods. The average structural deviation achieved by the TMFFs was almost twice that obtained with the hybrid method. The TMFF approach was extended by exploring the accuracy of a more general TMFF (GTMFF), which involved fitting the force-field parameters to the reference data for all three molecules simultaneously. This GTMFF was slightly less accurate than the individual TMFFs but still of sufficient accuracy to be used in CSP. A study of the isostructural relationships between these molecules and their crystal lattices revealed a potential polymorph of one of the compounds that has not been observed experimentally and that may be accessible in a thorough polymorph screen, through seeding, or through the use of a suitable tailor-made additive.