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Rapid structure determination of molecular solids using chemical shifts directed by unambiguous prior constraints

Rapid structure determination of molecular solids using chemical shifts directed by unambiguous prior constraints
Rapid structure determination of molecular solids using chemical shifts directed by unambiguous prior constraints
NMR based crystallography approaches involving the combination of crystal structure prediction methods, ab-initio calculated chemical shifts and solid-state NMR experiments are a powerful approach for crystal structure determination of microcrystalline powders. However, currently structural information obtained from solid state NMR is usually included only after a set of candidate crystal structures has already been independently generated, starting from a set of single molecule conformations. Here, we show with the case of ampicillin that this can lead to failure of structure determination. We propose a crystal structure determination method that includes experimental constraints during conformer selection. In order to overcome the problem that experimental measurements on the crystalline samples are not obviously translatable to restrict the single molecule conformational space, we propose constraints based on the analysis of absent cross-peaks in solidstate NMR correlation experiments. We show that these absences provide unambiguous structural constraints on both the crystal structure and the gas phase conformations, and therefore can be used for unambiguous selection. The approach is parameterized on the crystal structure determination of flutamide, flufenamic acid, and cocaine, where we reduce the computational cost by around 50%. Most importantly, the method is then shown to correctly determine the crystal structure of ampicillin, which would have failed using current methods
because it adopts a high energy conformer in its crystal structure. The average positional RMSE on the NMR powder structure is 〈푟_av〉 = 0.176 Å, which corresponds to an average equivalent displacement parameter 푈_eq = 0.0103 Å2.
0002-7863
Hofstetter, Albert
ff05c128-e1e1-41ec-95be-b9a8a5737b9b
Balodis, Martins
f6183671-8917-4643-b0ed-23ab3273c89b
Paruzzo, Federico M.
d2a5e336-85d3-4858-a86d-ab5febba205f
Widdifield, Cory M.
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Stevanato, Gabriele
9f91c4af-235c-4353-b840-9a62770044a3
Pinon, Arthur C.
5b1b7b59-d10f-4531-8d66-2c5d47293818
Bygrave, Peter
5b60f2a0-1477-43f6-a6a4-aa5a2804a549
Day, Graeme M.
e3be79ba-ad12-4461-b735-74d5c4355636
Emsley, Lyndon
21503ed8-53b1-44b4-ad7c-09a661bc667a
Hofstetter, Albert
ff05c128-e1e1-41ec-95be-b9a8a5737b9b
Balodis, Martins
f6183671-8917-4643-b0ed-23ab3273c89b
Paruzzo, Federico M.
d2a5e336-85d3-4858-a86d-ab5febba205f
Widdifield, Cory M.
4422f22e-a7bf-4a88-802a-9d65499fdb52
Stevanato, Gabriele
9f91c4af-235c-4353-b840-9a62770044a3
Pinon, Arthur C.
5b1b7b59-d10f-4531-8d66-2c5d47293818
Bygrave, Peter
5b60f2a0-1477-43f6-a6a4-aa5a2804a549
Day, Graeme M.
e3be79ba-ad12-4461-b735-74d5c4355636
Emsley, Lyndon
21503ed8-53b1-44b4-ad7c-09a661bc667a

Hofstetter, Albert, Balodis, Martins, Paruzzo, Federico M., Widdifield, Cory M., Stevanato, Gabriele, Pinon, Arthur C., Bygrave, Peter, Day, Graeme M. and Emsley, Lyndon (2019) Rapid structure determination of molecular solids using chemical shifts directed by unambiguous prior constraints. Journal of the American Chemical Society. (doi:10.1021/jacs.9b03908).

Record type: Article

Abstract

NMR based crystallography approaches involving the combination of crystal structure prediction methods, ab-initio calculated chemical shifts and solid-state NMR experiments are a powerful approach for crystal structure determination of microcrystalline powders. However, currently structural information obtained from solid state NMR is usually included only after a set of candidate crystal structures has already been independently generated, starting from a set of single molecule conformations. Here, we show with the case of ampicillin that this can lead to failure of structure determination. We propose a crystal structure determination method that includes experimental constraints during conformer selection. In order to overcome the problem that experimental measurements on the crystalline samples are not obviously translatable to restrict the single molecule conformational space, we propose constraints based on the analysis of absent cross-peaks in solidstate NMR correlation experiments. We show that these absences provide unambiguous structural constraints on both the crystal structure and the gas phase conformations, and therefore can be used for unambiguous selection. The approach is parameterized on the crystal structure determination of flutamide, flufenamic acid, and cocaine, where we reduce the computational cost by around 50%. Most importantly, the method is then shown to correctly determine the crystal structure of ampicillin, which would have failed using current methods
because it adopts a high energy conformer in its crystal structure. The average positional RMSE on the NMR powder structure is 〈푟_av〉 = 0.176 Å, which corresponds to an average equivalent displacement parameter 푈_eq = 0.0103 Å2.

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More information

Accepted/In Press date: 21 May 2019
e-pub ahead of print date: 22 May 2019

Identifiers

Local EPrints ID: 431254
URI: http://eprints.soton.ac.uk/id/eprint/431254
ISSN: 0002-7863
PURE UUID: 08ea494b-48ec-4046-baf9-448929c0915e
ORCID for Graeme M. Day: ORCID iD orcid.org/0000-0001-8396-2771

Catalogue record

Date deposited: 28 May 2019 16:30
Last modified: 17 Dec 2019 01:38

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