Beyond Rotatable Bond Counts: Capturing 3D Conformational Flexibility in a Single Descriptor

Nov 242016
 

J. Chem. Inf. Model., 2016, 56 (12), 2347–2352 doi: 10.1021/acs.jcim.6b00565

A new molecular descriptor, nConf20, based on chemical connectivity, is presented which captures the accessible conformational space of a molecule. Currently the best available 2-dimensional descriptors for quantifying the flexibility of a particular molecule are the rotatable bond count (RBC) and the Kier flexibility index. We present a descriptor which captures this information by sampling the conformational space of a molecule using the RDKit conformer generator. Flexibility has previously been identified as a key feature in determining whether a molecule is likely to crystallize or not. For this application, nConf20 significantly outperforms previously reported single-variable classifiers and also assists rule-based analysis of black-box machine learning classification algorithms.

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Hydrogen-​Bonded Homoleptic Fluoride-​Diarylurea Complexes: Structure, Reactivity, and Coordinating Power

Sep 232016
 

Journal of the American Chemical Society 2016, 138(40), 13314-13325 [doi:10.1021/jacs.6b07501]

Hydrogen bonding with fluoride is a key interaction encountered when analyzing the mode of action of 5′-​fluoro-​5′-​deoxyadenosine synthase, the only known enzyme capable of catalyzing the formation of a C-​F bond from F–​. Further understanding of the effect of hydrogen bonding on the structure and reactivity of complexed fluoride is therefore important for catalysis and numerous other applications, such as anion supramol. chem. Herein we disclose a detailed study examg. the structure of 18 novel urea-​fluoride complexes in the solid state, by X-​ray and neutron diffraction, and in soln. phase and explore the reactivity of these complexes as a fluoride source in SN2 chem. Exptl. data show that the structure, coordination strength, and reactivity of the urea-​fluoride complexes are tunable by modifying substituents on the urea receptor. Hammett anal. of aryl groups on the urea indicates that fluoride binding is dependent on σp and σm parameters with stronger binding being obsd. for electron-​deficient urea ligands. For the first time, defined urea-​fluoride complexes are used as fluoride-​binding reagents for the nucleophilic substitution of a model alkyl bromide. The reaction is slower in comparison with known alc.-​fluoride complexes, but SN2 is largely favored over E2, at a ratio surpassing all hydrogen-​bonded complexes documented in the literature for the model alkyl bromide employed. Increased second-​order rate consts. at higher diln. support the hypothesis that the reactive species is a 1:1 urea-​fluoride complex of type [UF]–​ (U = urea) resulting from partial dissocn. of the parent compd. [U2F]​–​. The dissocn. processes can be quantified through a combination of UV and NMR assays, including DOSY and HOESY analyses that illuminate the complexation state and H-​bonding in soln.

Fluoride–urea complex

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Why direct and post-refinement determinations of absolute structure may give different results

Sep 192016
 

Acta. Cryst. (2016) B72 661-683 (Feature Article) [ doi:10.1107/S2052520616012890 ]

surfaceDirect determination of the Flack parameter as part of the structure refinement procedure usually gives different, though similar, values to post-refinement methods. The source of this discrepancy has been probed by analysing a range of data sets taken from the recent literature. Most significantly, it was observed that the directly refined Flack (x) parameter and its standard uncertainty are usually not much influenced by changes in the refinement weighting schemes, but if they are then there are probably problems with the data or model. Post-refinement analyses give Flack parameters strongly influenced by the choice of weights. Weights derived from those used in the main least squares lead to post-refinement estimates of the Flack parameters and their standard uncertainties very similar to those obtained by direct refinement. Weights derived from the variances of the observed structure amplitudes are more appropriate and often yield post-refinement Flack parameters similar to those from direct refinement, but always with lower standard uncertainties. Substantial disagreement between direct and post-refinement determinations are strongly indicative of problems with the data, which may be difficult to identify. Examples drawn from 28 structure determinations are provided showing a range of different underlying problems. It seems likely that post-refinement methods taking into account the slope of the normal probability plot are currently the most robust estimators of absolute structure and should be reported along with the directly refined values.

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Report on the sixth blind test of organic crystal structure prediction methods

Aug 022016
 

Acta. Cryst. (2016) B72(4), 439-459 [ doi:10.1107/S2052520616007447 ] A. M. Reilly, R. I. Cooper, C. S. Adjiman, S. Bhattacharya, A. D. Boese, J. G. Brandenburg, P. J. Bygrave, R. Bylsma, J. E. Campbell, R. Car, D. H. Case, R. Chadha, J. C. Cole, K. Cosburn, H. M. Cuppen, F. Curtis, G. M. Day, R. A. DiStasio Jr, A. Dzyabchenko, B. P. van Eijck, D. M. Elking, J. A. van den Ende, J. C. Facelli, M. B. Ferraro, L. Fusti-Molnar, C.-A. Gatsiou, T. S. Gee, R. de Gelder, L. M. Ghiringhelli, H. Goto, S. Grimme, R. Guo, D. W. M. Hofmann, J. Hoja, R. K. Hylton, L. Iuzzolino, W. Jankiewicz, D. T. de Jong, J. Kendrick, N. J. J. de Klerk, H.-Y. Ko, L. N. Kuleshova, X. Li, S. Lohani, F. J. J. Leusen, A. M. Lund, J. Lv, Y. Ma, N. Marom, A. E. Masunov, P. McCabe, D. P. McMahon, H. Meekes, M. P. Metz, A. J. Misquitta, S. Mohamed, B. Monserrat, R. J. Needs, M. A. Neumann, J. Nyman, S. Obata, H. Oberhofer, A. R. Oganov, A. M. Orendt, G. I. Pagola, C. C. Pantelides, C. J. Pickard, R. Podeszwa, L. S. Price, S. L. Price, A. Pulido, M. G. Read, K. Reuter, E. Schneider, C. Schober, G. P. Shields, P. Singh, I. J. Sugden, K. Szalewicz, C. R. Taylor, A. Tkatchenko, M. E. Tuckerman, F. Vacarro, M. Vasileiadis, A. Vazquez-Mayagoitia, L. Vogt, Y. Wang, R. E. Watson, G. A. de Wijs, J. Yang, Q. Zhu and C. R. Groom

predictionsThe 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 flexible molecule. This blind test has seen substantial growth in the number of participants, with the broad range of prediction methods giving a unique insight into the state of the art in the field.

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Mr. Alex Mercer

Jun 232016
 

mercerAlex is undertaking a research project attempting to automatically model severe disorder with crystal structures using a Monte-Carlo approach. Alex is firmly in the computational side of the research group avoiding any crystallisation or actual diffraction at all costs.

 

Mr. Oliver Robshaw

Jun 232016
 

robbieOliver joins the group undertaking a project searching for trends and correlations between crystal structure similarity and molecular similarity. He will also attempt to extend his analysis to co-crystal formation rules for which he will undertake and analyse a significant number of combinatorial experiments.

Outside work he spends much of his free time at the bank in his role as treasurer of various adventurous University societies including caving, orienteering and scuba diving.

Ms. Katie McInally

Jun 232016
 

katieKatie is investigating crystallisation properties of different classes of materials. The results will be compared with crystallisability predictions carried out as part of Jerome Wicker‘s Part II and DPhil research, and previous measurement of molecular crystallisation properties.

Katie undertook rapid prototyping of her crystallisation apparatus using Lego, LEDs, plenty of solder and a Raspberry Pi computer. After work she enjoys her role as Safety Officer of the University pistol club.

Ms. Jo Baker

Jun 232016
 

baker16Jo is investigating crystalline materials which undergo light-induced changes in the solid-state. We will make use of these materials as model systems for in situ tracking by diffraction of conformational changes and reactions which can be triggered by external stimuli.

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