Crystal packing predictions of the alpha-amino acids: methods assessment and structural observations

Day, Graeme M.; Cooper, Timothy G.

doi:10.1039/c002213f

Cited by 32 publications

(39 citation statements)

References 41 publications

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“…Crystal structures of Phe were predicted using a global lattice energy exploration approach, with the aim of finding all low energy crystal packings of the molecule within the space group symmetries considered in the study. The overall strategy for predicting the crystal structures of flexible molecules has been fully described elsewhere 34 and has been shown to work well on a set of single-component 35 and two-component 36 h. ranking the structures in order of increasing total (inter + intramolecular) energy.…”

Section: Crystal Structure Predictionmentioning

confidence: 99%

The Plot Thickens: Gelation by Phenylalanine in Water and Dimethyl Sulfoxide

Nartowski

Ramalhete

Martin

et al. 2017

Crystal Growth & Design

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Phenylalanine (Phe) is an amino acid of great interest as coupling of an aromatic group with a chiral hydrophilic region imparts a number of unique properties. Recently there has been an increased interest in the crystalline and gel forms of this compound, part as a result of the complex and undetermined structures of the resulting materials and the relationship of the solid forms of Phe with the disease phenylketonuria. In this report, we highlight the relationship between gelation, crystallization, and the dynamics of self-assembly processes of Phe. We do this by describing the gelation of the amino acid, the gel to crystal relationship, crystal structure predictions for this relatively simple compound, and the dynamics of assembly as determined by NMR in both water and dimethyl sulfoxide. This will provide guidance to future research into Phe assemblies, possible treatments for phenylketonuria, and diseases related to formation of amyloid-like fibers

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Section: Crystal Structure Predictionmentioning

confidence: 99%

The Plot Thickens: Gelation by Phenylalanine in Water and Dimethyl Sulfoxide

Nartowski

Ramalhete

Martin

et al. 2017

Crystal Growth & Design

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“…Analysis of the predicted structures provides information about the most prevalent intermolecular interactions and supramolecular synthons responsible for the formation of the crystal. The experimental structure may then be determined by validating the predicted structure against experimental data, such as X‐ray powder patterns, TEM electron diffraction data, or solid‐state NMR spectra.…”

Section: Resultsmentioning

confidence: 99%

Rationalization of the Color Properties of Fluorescein in the Solid State: A Combined Computational and Experimental Study

Arhangelskis

Eddleston

Reid

et al. 2016

Chemistry A European J

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Fluorescein is known to exist in three tautomeric forms defined as quinoid, zwitterionic, and lactoid. In the solid state, the quinoid and zwitterionic forms give rise to red and yellow materials, respectively. The lactoid form has not been crystallized pure, although its cocrystal and solvate forms exhibit colors ranging from yellow to green. An explanation for the observed colors of the crystals is found using a combination of UV/Vis spectroscopy and plane‐wave DFT calculations. The role of cocrystal coformers in modifying crystal color is also established. Several new crystal structures are determined using a combination of X‐ray and electron diffraction, solid‐state NMR spectroscopy, and crystal structure prediction (CSP). The protocol presented herein may be used to predict color properties of materials prior to their synthesis.

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“…However, the enormous computational cost makes this impractical for use in accurate CSP studies of large exible molecules with current computer resources. Full DFTB3-D3 optimisations are signicantly better than xed cell optimisations of selected torsion angles with a transferable force-eld, a previously used intermediate step in CSP for exible molecules, 43,44,50 where the energies were discarded. In practice, theoretical accuracy, which is very dependent on the molecule and range of crystal structures, has to be compromised by the huge number of structures that need to be considered, and the need to make such studies affordable for larger pharmaceutical studies.…”

Section: Discussionmentioning

confidence: 99%

“…A possible solution is the use of an intermediate optimisation method, which can bridge the gap between the simple models used to generate the crystal structures and the more accurate ones used to generate an accurate nal energy ranking. For exible molecules, several intermediate methods are used in different CSP workows, such as optimising some torsion angles with a transferable force-eld to improve the molecular conformation geometries, 43,44 single-point energy calculations with a more accurate description of the intra-and intermolecular interactions 18,20 or partial lattice energy optimisations. 1,22 Recently, semi-empirical QM methods have been applied to large chemical and biochemical systems; 45,46 these methods do not have the transferability problems of standard force elds but are signicantly less demanding than other QM methods.…”

Section: Introductionmentioning

confidence: 99%

Crystal structure prediction of flexible pharmaceutical-like molecules: density functional tight-binding as an intermediate optimisation method and for free energy estimation

et al. 2018

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Successful methodologies for theoretical crystal structure prediction (CSP) on flexible pharmaceutical-like organic molecules explore the lattice energy surface to find a set of plausible crystal structures. The initial search stages of CSP studies use relatively simple lattice energy approximations as hundreds of thousands of minima have to be considered. These generated crystal structures often have poor molecular geometries, as well as inaccurate lattice energy rankings, and performing reasonably accurate but computationally affordable optimisations of the crystal structures generated in a search would be highly desirable. Here, we seek to explore whether semi-empirical quantum-mechanical methods can perform this task. We employed the dispersion-corrected tight-binding Hamiltonian (DFTB3-D3) to relax all the inter- and intra-molecular degrees of freedom of several thousands of generated crystal structures of five pharmaceutical-like molecules, saving a large amount of computational effort compared to earlier studies. The computational cost scales better with molecular size and flexibility than other CSP methods, suggesting that it could be extended to even larger and more flexible molecules. On average, this optimisation improved the average reproduction of the eight experimental crystal structures (RMSD15) and experimental conformers (RMSD1) by 4% and 23%, respectively. The intermolecular interactions were then further optimised using distributed multipoles, derived from the molecular wave-functions, to accurately describe the electrostatic components of the intermolecular energies. In all cases, the experimental crystal structures are close to the top of the lattice energy ranking. Phonon calculations on some of the lowest energy structures were also performed with DFTB3-D3 methods to calculate the vibrational component of the Helmholtz free energy, providing further insights into the solid-state behaviour of the target molecules. We conclude that DFTB3-D3 is a cost-effective method for optimising flexible molecules, bridging the gap between the approximate methods used in CSP searches for generating crystal structures and more accurate methods required in the final energy ranking.

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Crystal packing predictions of the alpha-amino acids: methods assessment and structural observations

Cited by 32 publications

References 41 publications

The Plot Thickens: Gelation by Phenylalanine in Water and Dimethyl Sulfoxide

The Plot Thickens: Gelation by Phenylalanine in Water and Dimethyl Sulfoxide

Rationalization of the Color Properties of Fluorescein in the Solid State: A Combined Computational and Experimental Study

Crystal structure prediction of flexible pharmaceutical-like molecules: density functional tight-binding as an intermediate optimisation method and for free energy estimation

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