Acta Crystallographica Section B
`Structural
`Science
`
`ISSN 0108-7681
`
`W. D. Sam Motherwell,a*
`Herman L. Ammon,b Jack D.
`Dunitz,c Alexander
`Dzyabchenko,d Peter Erk,e
`Angelo Gavezzotti,f
`Detlef W. M. Hofmann,g
`Frank J. J. Leusen,h Jos P. M.
`Lommerse,i Wijnand T. M.
`Mooij,h,p Sarah L. Price,j Harold
`Scheraga,k Bernd Schweizer,c
`Martin U. Schmidt,l Bouke P. van
`Eijck,m Paul Verwern and
`Donald E. Williamso²
`
`aCambridge Crystallographic Data Centre, 12
`Union Road, Cambridge CB2 1EZ, UK,
`bDepartment of Chemistry and Biochemistry,
`University of Maryland, College Park, MD
`20742-2021, USA, cOrganic Chemical Labora-
`tory, ETH-Zurich, CH-8093 Zurich, Switzerland,
`dKarpov Institute of Physical Chemistry, Voront-
`sovo pole 10, 103064 Moscow, Russia,
`ePerformance Chemicals Research, BASF AG,
`67056 Ludwigshafen, Germany, fDipartmento
`di Chimica Strutturale e Stereochimica Inorga-
`nica, via Venezian 21, 20133 Milano, Italy,
`gGMD-SCAI, Schloss Berlinghoven, D-53754 St
`Augustin, Germany, hAccelrys Ltd, 230/250 The
`Quorum, Barnwell Road, Cambridge CB5 8RE,
`UK, iDoelenstraat 17, 5348 JR Oss, The
`Netherlands, jCentre for Theoretical and
`Computational Chemistry, Department of
`Chemistry, University College, 20 Gordon
`Street, London WC1H 0AJ, UK, kBaker Labora-
`tory of Chemistry, Cornell University, Ithaca, NY
`14853-1301, USA, lClariant GmbH, Pigment
`Technology Research, G834, D-65926 Frankfurt
`am Main, Germany, mBijvoet Centre for
`Biomolecular Research, Utrecht University,
`Padualaan 8, 3584 CH Utrecht, The Nether-
`lands, nSolid State Chemistry Group and CMBI,
`University of Nijmegen, PO Box 9010, 6500 GL
`Nijmegen, The Netherlands, oDepartment of
`Chemistry, University of Louisville, Louisville,
`KY 40292-2001, USA, and pAstex Technology
`Ltd, 250 Cambridge Science Park, Cambridge
`CB4 0WE, UK
`
`² DeceasedCorrespondence e-mail:
`² Deceased
`motherwell@ccdc.cam.ac.uk
`
`Correspondence e-mail:
`motherwell@ccdc.cam.ac.uk
`
`research papers
`
`Crystal structure prediction of small organic
`molecules: a second blind test
`
`Received 14 January 2002
`Accepted 27 March 2002
`
`Dedicated in memoriam Jan
`Kroon
`
`The ®rst collaborative workshop on crystal structure predic-
`tion (CSP1999) has been followed by a second workshop
`(CSP2001) held at the Cambridge Crystallographic Data
`Centre. The 17 participants were given only the chemical
`diagram for three organic molecules and were invited to test
`their prediction programs within a range of named common
`space groups. Several different computer programs were used,
`using the methodology wherein a molecular model is used to
`construct theoretical crystal structures in given space groups,
`and prediction is usually based on the minimum calculated
`lattice energy. A maximum of three predictions were allowed
`per molecule. The results showed two correct predictions for
`the ®rst molecule, four for the second molecule and none for
`the third molecule (which had torsional ¯exibility). The
`correct structure was often present in the sorted low-energy
`lists from the participants but at a ranking position greater
`than three. The use of non-indexed powder diffraction data
`was investigated in a secondary test, after completion of the ab
`initio submissions. Although no one method can be said to be
`completely reliable, this workshop gives an objective measure
`of the success and failure of current methodologies.
`
`1. Introduction
`
`Two major challenges appear to confront the predictive ability
`of theoretical and computational chemistry today: one is
`protein folding and the other is crystallization of organic
`compounds. There are obvious similarities. Both involve
`delicate balances between attractions and repulsions at the
`atomic level, between potential energy and entropic contri-
`butions to the free energy, and between thermodynamic and
`kinetic factors. Blind tests on the folding of proteins have been
`conducted in recent times (Orengo et al., 1999). Here we
`report on a similar venture in crystal structure prediction
`(CSP) carried out in two stages in 1999 and 2001. Although
`early lack of progress in CSP was termed a `continuing
`scandal' in Nature in 1988 (Maddox, 1988), and in spite of
`isolated claims of minor victories, the problem is now gener-
`ally recognized to be much more dif®cult than had been
`apparent. It is now seen to be not so much a matter of
`generating stable crystal structures but rather one of selecting
`one or more from many almost equi-energetic possibilities.
`Our successes and failures point the way to a better under-
`standing of the polymorphism phenomenon and also have
`practical implications for crystal engineering and design.
`
`2. Approach and methodology
`
`# 2002 International Union of Crystallography
`# 2002 International Union of Crystallography
`Printed in Great Britain ± all rights reserved
`Printed in Great Britain ± all rights reserved
`
`This paper reports on the results of a second blind test, known
`as CSP2001, which was part of a collaborative workshop held
`
`Acta Cryst. (2002). B58, 647±661
`
`Motherwell et al.
`
`(cid:15) Crystal structure prediction 647
`
`SENJU EXHIBIT 2037
`INNOPHARMA v. SENJU
`IPR2015-00903
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`research papers
`
`at the Cambridge Crystallographic Data Centre (CCDC) in
`May 2001. The results of the ®rst blind test, CSP1999, have
`already been published (Lommerse et al., 2000). The
`arrangement of the blind test was as in CSP1999. Personal
`invitations were sent to about 25 researchers known to be
`active in the ®eld and a total of 18 individuals agreed to
`participate. The list of unpublished structures was collected by
`personal contacts with about 30 laboratories known to be
`active in the small-molecule ®eld. To give a reasonable chance
`of success within the practical computation limits of known
`computer programs, the maximum number of atoms including
`H atoms was set as 40; the space group was required to be in
`one of the ten most frequent as recorded in the Cambridge
`Structural Database (CSD) (Allen & Kennard, 1993),
`i.e.
`P21/c, P(cid:22)1, P212121, C2/c, P21, Pbca, Pna21, Cc, Pbcn and C2 (in
`CSD frequency order); there should be one molecule per
`asymmetric unit and no solvent molecules or co-crystals. It was
`speci®ed to the experimentalists that there should be no
`disorder, and the positions of all H atoms should be located
`experimentally. There were three categories of perceived
`dif®culty for prediction:
`(i) rigid molecule with only C, H, N and O atoms, less than
`25 atoms,
`(ii) rigid molecule with some less common elements (e.g.
`Br), less than 30 atoms,
`(iii) ¯exible molecule with two degrees of acyclic torsional
`freedom, less than 40 atoms.
`An independent referee, Professor Tony Kirby, University
`Chemical Laboratory, Cambridge, was asked to select one
`molecule from each category and, if possible, to avoid mole-
`cules likely to be of near-planar conformation, as this turned
`out to be a bias in the CSP1999 selection. The referee had no
`access to the space group or crystal structure information, only
`to a list of chemical diagrams. The selected three chemical
`diagrams, IV, V and VI (Fig. 1), were sent by e-mail to the
`participants on 11 October 2000. The participants were asked
`to submit a maximum of three prediction structures for each
`molecule to the referee by midnight of 25 March 2001, with
`reasons for their selection and presentation in order of
`con®dence. These are referred to in this paper as the `ab initio
`predictions'.
`An optional secondary test of prediction was also arranged,
`where the participants were supplied with simulated X-ray
`powder diffraction patterns for each molecule as extra infor-
`mation. They were given a second deadline date of 11 April
`2001. The patterns were generated by CCDC after obtaining
`the experimental coordinates from the referee on 26 March
`2001. These secondary submissions are known as the `powder-
`assisted predictions' and are given in a separate section
`towards the end of this paper. On 12 April 2001, the experi-
`mental crystal structures were released to all participants,
`giving some time for post-analysis and preparation for the
`workshop meeting held in Cambridge on 10±11 May 2001.
`To assist the reader in assessing the overall success and
`failure rate in these tests, the results of the CSP1999 workshop
`have been included in this paper. The full list of molecules for
`both workshops (Fig. 1), the full range of computer program
`
`methodology (Table 1) and a summary of the results (Table 2)
`are given as combined tables for CSP1999 and CSP2001.
`
`3. Methodology
`
`Methods in the CSP tests are summarized in Table 1.
`Comprehensive reviews of computer methodology for crystal
`structure prediction have been published where many refer-
`ences are given to detailed publications (Gdanitz, 1997;
`Verwer & Leusen, 1998). All the methods involve three stages:
`(a) construct a three-dimensional molecular model either
`by molecular mechanics methods or by analogy with other
`CSD structures;
`(b) search through many thousands of hypothetical crystal
`structures built from the trial molecule in various space
`groups, including some searches that did not assume symmetry
`constraints;
`(c) select structures according to some criterion, usually the
`calculated lattice energy.
`The search algorithms are quite diverse, and force ®elds
`range from simple transferable atom±atom potentials to
`elaborate computer-intensive models for the electrostatic and
`other contributions to the intermolecular potential. One or
`two models included explicit allowance for polarization
`effects. The most common selection criterion is the global
`minimum in lattice energy, and the most important discovery
`for CSP within the past decade is the recognition that many
`discrete structural possibilities exist within an energy window
`of only a few kJ mol(cid:255)1 above the global minimum. For
`example, for acetic acid there are about 100 calculated struc-
`tures within 5 kJ mol(cid:255)1 (Mooij et al., 1998), although only one
`polymorph at ambient pressure has been found experimen-
`
`Figure 1
`The molecular diagrams given to the participants in the CSP workshops
`(I±III, VII for CSP1999; IV±VI for CSP2001). Experimental structures
`references: I (Boese & Garbarczyk, 1998), II (Blake et al., 1999), III
`(Clegg et al., 2001), IV (Howie & Skakle, 2001), V (Fronczek & Garcia,
`2001), VI (Hursthouse, 2001), VII (Boese et al., 1999).
`
`648 Motherwell et al.
`
`(cid:15) Crystal structure prediction
`
`Acta Cryst. (2002). B58, 647±661
`
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`

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`research papers
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`Table 1
`Overview of methodologies applied for crystal structure prediction for the blind test.
`
`Contributor
`
`Molecules attempted
`
`Program/approach
`
`Reference Molecular model
`
`Search generation
`
`Methods employing lattice-energy minimization for generation of structures
`Gavezzotti
`III, V
`ZIP-PROMET
`Schweizer & Dunitz
`I, IV
`ZIP-PROMET
`Williams
`I±VII
`MPA
`Erk
`IV±VI
`SySe and PP
`van Eijck
`I, III±VII
`UPACK
`Dzyabchenko
`IV±VI
`PMC
`Schmidt
`I±VI
`CRYSCA
`Ammon
`I±VI
`MOLPAK
`Price
`I±V
`DMAREL
`Scheraga
`IV±VI
`CRYSTALG
`Verwer & Leusen
`I±III, VII
`Polymorph Predictor (PP)
`Leusen
`IV±VI
`Polymorph Predictor (PP)
`Verwer
`IV±VI
`Polymorph Predictor (PP)
`Mooij
`I, III, VII
`Multipole crystal optimizer
`Mooij
`IV±VI
`Multipole crystal optimizer
`
`Methods based on statistical data from CSD
`Hofmann
`I±III
`IV±VI
`I±V, VII
`I±V, VII
`
`Lommerse
`Motherwell
`
`FlexCryst
`FlexCryst
`Packstar
`Rancel
`
`a
`a
`b
`c
`d
`e
`f
`g
`h
`i
`j
`j
`j
`k
`k
`
`l
`m
`n
`o
`
`Lattice energy/®tness function
`
`Rigid
`Rigid
`Flexible
`Flexible
`Flexible
`Flexible
`Flexible
`Rigid
`Rigid
`Flexible
`Flexible
`Flexible
`Flexible
`Flexible
`Flexible
`
`Rigid
`Rigid
`Rigid
`Rigid
`
`Stepwise construction of dimers and layers
`Stepwise construction of dimers and layers
`Lattman grid systematic
`Grid-based systematic
`Grid-based and random
`Symmetry-adapted grid systematic
`Random plus steepest descent
`Grid-based systematic
`Using MOLPAK
`Conformation family Monte Carlo
`Monte Carlo simulated annealing
`Monte Carlo simulated annealing
`Monte Carlo simulated annealing
`By van Eijck (UPACK)
`By Leusen & Verwer (PP)
`
`Grid-based systematic
`Grid-based systematic
`Monte Carlo simulated annealing
`Genetic algorithm
`
`Contributor
`
`Electrostatic
`
`Other
`
`Other features used to select three submissions
`
`Methods employing lattice-energy minimization for generation of structures
`Gavezzotti
`None
`Schweizer & Dunitz
`Atom charges
`Williams
`Atom charges + extra sites
`Erk
`Atom charges
`van Eijck
`Atom charges
`Dzyabchenko
`Atom charges
`Schmidt
`Atom charges
`Ammon
`Atom charges
`Price
`Atom multipoles
`Scheraga
`Atom charges
`Verwer & Leusen
`Atom charges
`Leusen
`Atom charges
`Verwer
`Atom charges
`Mooij
`Atom multipoles
`Mooij
`Atom multipoles
`
`Empirical
`6-exp
`6-exp
`6-exp
`6-exp or 6±12
`6-exp or 6±12
`6-exp
`6-exp
`Empirical /derived
`6-exp or 6±12
`Dreiding 6±12
`CVFF 6±12
`Dreiding 6±12
`Ab initio 6-exp + polarization
`Dreiding 6-exp
`
`Free Energy
`
`Volume, chemical intuition
`Density
`Morphology and elastic constants
`
`Methods based on statistical data from CSD
`Hofmann
`
`Lommerse
`Motherwell
`
`Statistical potentials
`Trained potentials
`CSD group contacts
`None
`
`6-exp
`
`Energy plus ®tting of CSD contacts
`
`References: (a) Gavezzotti (1991); (b) Williams (1996); (c) Erk (1999); (d) van Eijck & Kroon (2000); (e) Dzyabchenko et al. (1999); (f) Schmidt & Englert (1996); (g) Holden et al.
`(1993); (h) Beyer et al. (2001); (i) Pillardy et al. (2001); (j) Verwer & Leusen (1998); (k) Mooij et al. (1999); (l) Hofmann & Lengauer (1997); (m) Apostolakis et al. (2001); (n) Lommerse et
`al. (2000); (o) Motherwell (2001).
`
`tally. Most search methods included the `correct' structure
`somewhere in the list, but it was frequently not the structure
`with the lowest lattice energy. Besides, small changes in the
`potentials can reshuf¯e the energy ordering. Most calculated
`structures are `temperature-less'
`in the sense that no
`temperature is speci®ed in the computational procedure, but
`some include estimates of the free energy. There are also
`attempts to use pattern recognition based on the Cambridge
`Structural Database of experimentally determined molecular
`crystals. Although the importance of the kinetic aspects of
`crystal nucleation and growth is widely recognized, they
`remain largely unexplored.
`
`4. Overview of results
`
`The submitted results for the ab initio predictions are given for
`molecules IV (Table 3), V (Table 4) and VI (Table 5). For the
`combined tests CSP1999 and CSP2001, the correct predictions
`are summarized in Table 2. Since there were so many contri-
`butors who worked independently, it was thought best to
`provide ®rst an overview of the results (x4) and some general
`conclusions (x6). In the supplementary material,1 we provide
`
`1 Supplementary data for this paper are available from the IUCr electronic
`archives (Reference: BK0108). Services for accessing these data are described
`at the back of the journal.
`
`Acta Cryst. (2002). B58, 647±661
`
`Motherwell et al.
`
`(cid:15) Crystal structure prediction 649
`
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`

`
`research papers
`
`Table 2
`Summary of successful predictions.
`
`Molecule
`
`P
`
`Space group
`
`The experimental structures are labelled Expt and printed in bold. For the experimental structures, P gives the number of successful predictions, and for the
`predicted structures, P is the order of con®dence in the three submissions allowed. RMSD-Pack is the calculated r.m.s. deviation of the non-H atom positions from
`experimental positions. The decision as to a correct solution has been based on a visual assessment of the packing diagrams.
`(cid:12) ((cid:14))
`
`a (AÊ )
`
`b (AÊ )
`
`c (AÊ )
`
`RMSD-Pack (AÊ )
`
`I Expt stable
`I Expt Metastable
`Schweizer
`Williams
`Verwer & Leusen
`van Eijck
`II Expt
`Verwer & Leusen
`III Expt
`van Eijck
`IV Expt
`Leusen
`Mooij
`V Expt
`Price
`Williams²
`van Eijck³
`Ammon§
`VI Expt
`VII Expt
`Mooij
`
`0
`4
`1
`1
`1
`3
`1
`2
`1
`1
`3
`3
`2
`3
`1
`3
`1
`1
`0
`1
`1
`
`P21/c
`Pbca
`Pbca
`Pbca
`Pbca
`Pbca
`P21/n
`P21/n
`P21/c
`P21/c
`P21/c
`P21/c
`P21/c
`P212121
`P212121
`P212121
`P212121
`P212121
`P21/c
`P21/n
`P21/n
`
`4.954
`5.309
`5.182
`5.125
`5.372
`5.276
`7.516
`7.234
`6.835
`6.763
`9.388
`9.182
`9.229
`7.264
`7.177
`6.930
`7.119
`7.128
`8.251
`4.148
`4.057
`
`9.845
`12.648
`12.554
`12.503
`12.570
`12.468
`8.322
`8.299
`7.634
`7.758
`10.606
`10.509
`10.406
`10.639
`10.413
`10.660
`9.984
`10.394
`8.964
`12.612
`12.568
`
`9.679
`14.544
`14.336
`14.104
`15.131
`14.390
`9.059
`9.210
`21.422
`20.940
`7.704
`8.024
`7.963
`15.633
`16.223
`15.580
`15.891
`16.354
`15.087
`6.977
`6.777
`
`90.57
`90
`90
`90
`90
`90
`101.19
`104.53
`96.45
`98.32
`95.03
`83.02
`96.13
`90
`90
`90
`90
`90
`91.21
`91.28
`91.66
`
`0.204
`0.277
`0.231
`0.525
`
`0.427
`
`0.214
`
`0.261
`0.200
`
`0.347
`0.263
`0.777
`0.364
`
`0.163
`
`³ Correct packing but a large value 0.777 is due to molecular conformation
`² Williams submitted a structure in space group Cc, which is an error. If ignored, this makes the rank P = 2.
`differences because of an inadequate force ®eld.
`§ Although strictly speaking not allowed within the rules of the blind test, this result was the global minimum within chiral space
`groups. Structures in centrosymmetric space groups for the racemate were submitted in error.
`
`details of calculations and discussions prepared by each
`participant, under a named author subsection.
`
`4.1. Description of the experimental structures
`
`A few comments on the experimentally determined struc-
`tures are now given to demonstrate some of the challenges of
`prediction.
`Compound IV (Howie & Skakle, 2001), in P21/a, shows
`hydrogen bonding in the packing diagram in Fig. 2. Inspection
`of related molecules in the CSD ± those containing the
`
`CHÐCOÐNHÐCOÐCH group in a ring system, with no
`other strong hydrogen-bond donors or acceptors ± shows both
`dimer R2,2,(8) and catemer S1,1,(4) hydrogen-bond motifs
`(Allen et al., 1999). The observed hydrogen-bond motif is a
`catemer, ÐNH(cid:1)(cid:1)(cid:1)OCÐ mediated by the glide-plane operator
`in the a direction, and is almost exactly planar with N and O
`deviations of ca. 0.15 AÊ from the least-squares plane through
`the C, N, O and H atoms. The NÐH(cid:1)(cid:1)(cid:1)O distance of 1.973 AÊ is
`typical from CSD surveys, with almost optimal geometry:
`angles NÐH(cid:1)(cid:1)(cid:1)O = 171(cid:14) and H(cid:1)(cid:1)(cid:1)O C = 129(cid:14), calculated
`using a normalized neutron NÐH distance of 1.009 AÊ . The
`
`Figure 2
`Packing diagram for IV (a) showing hydrogen-bonded chains and (b) showing packing of chains.
`
`650 Motherwell et al.
`
`(cid:15) Crystal structure prediction
`
`Acta Cryst. (2002). B58, 647±661
`
`Page 4 of 15
`
`

`
`other carbonyl O takes no part in hydrogen bonding. It was
`noted that there is a rather short intermolecular H(cid:1)(cid:1)(cid:1)H
`contact of 2.118 AÊ between methylene groups related by a
`crystallographic centre of symmetry, but such contacts are
`found in some CSD structures of rather similarly sized mole-
`cules (e.g. AZTCDO10 2.199, BADNUP 2.157, 2.178).
`Compound V (Fronczek & Garcia, 2001), in P212121 and
`known in advance to be a pure enantiomer, has no strong
`hydrogen-bonding groups, and the packing diagram (Fig. 3)
`does not show any particularly dominant group±group inter-
`actions. Intermolecular contacts are normal compared to
`similar molecules in the CSD; the O atoms have several
`CÐH(cid:1)(cid:1)(cid:1)O contacts (2.365, 2.381, 2.425, 2.593, 2.646 AÊ )
`substantially below the van der Waals radius sum. The Br
`atoms show no close contacts but do form a Br(cid:1)(cid:1)(cid:1)Br chain
`distance of 4.427 AÊ using the screw axis along a. The ®ve-
`membered ring containing S and N is infrequent in the CSD,
`but
`there is an entry for the de-brominated compound
`ROLBOJ, which has a similar ring conformation.
`is strongly
`in P21/c,
`Compound VI (Hursthouse, 2001),
`hydrogen bonded (Fig. 4), forming a ribbon network running
`in the b direction mediated by the screw axis. It is notable that
`all donor H atoms are satis®ed, and all acceptor O and N
`atoms are involved. It was observed that the bond lengths
`appear to be of low accuracy, despite the excellent hydrogen-
`
`research papers
`
`bonding scheme, and subsequent communication with the
`laboratory revealed that there was a problem with very small
`crystals and a very low number of collected intensities. It was
`requested that a constrained re®nement be made using the
`known phenyl geometry and isotropic temperature factors.
`The coordinate differences between the ®rst and second
`re®nements do not invalidate the accuracy of the packing
`arrangement for the purposes of this blind test. Apart from the
`two ¯exible torsional angles, an additional dif®culty for CSP
`was that the SÐN CÐN con®guration might be either cis or
`trans.
`
`4.2. Comparison of calculated structures with experimental
`
`A preliminary inspection of the submitted results using
`standard visualizer programs quickly revealed that many
`structures were completely different from the experimentally
`determined ones. The structures that visually seemed to show
`the same packing arrangement and similar cell dimensions
`were generally easy to accept as `correct' as regards the overall
`packing arrangement. As in the CSP1999 test, we used the
`comparison method by Lommerse (Lommerse et al., 2000) to
`compare the molecular coordination shell and derive an r.m.s.
`deviation for the non-H atoms for all atoms in the reference
`molecule and its 12 neighbours (RMSD-Pack; these calcula-
`tions were performed by Lommerse before the workshop
`event). The lists of unit cells, space groups and RMSD-Pack
`are given for molecules IV (Table 3), V (Table 4) and VI
`(Table 5).
`For correct structures in CSP1999, this ®gure was found to
`be in the range 0.163±0.525 AÊ . In practice, `incorrect' struc-
`tures show such a large RMSD that there is no problem in
`deciding; in this test, the range for correct structures was
`0.200±0.364 AÊ . Only one case was found where there was a
`dif®cult decision, with a larger RMSD of 0.777 (van Eijck
`structure V, rank 1). This structure has the same symmetry-
`related 12 neighbours in the molecular coordination shell as
`
`Figure 3
`Packing diagram for V. There is no strong hydrogen bonding, but several
`CÐH(cid:1)(cid:1)(cid:1)O contacts are apparent. All contacts less than the sum of the
`van der Waals radii are shown.
`
`Figure 4
`Packing diagram for VI. Selective view showing the hydrogen-bonding
`scheme, mediated by a screw axis along b. Note that all H donors are
`satisi®ed, and all acceptors have at least one H contact.
`
`Acta Cryst. (2002). B58, 647±661
`
`Motherwell et al.
`
`(cid:15) Crystal structure prediction 651
`
`Page 5 of 15
`
`

`
`research papers
`
`Table 3
`Submitted results for molecule IV.
`
`Results are presented in the space-group settings as submitted. Correct predictions are given in bold type. RMSD-Pack is calculated by the Lommerse method and
`is only given when a meaningful ®t could be found within a certain tolerance.
`
`RMSD-Pack (AÊ )
`
`0.261
`
`0.200
`
`Name
`
`Space group
`
`Experimental
`Ammon
`
`Dzyabchenko
`
`Erk
`
`Hofmann
`
`Leusen
`
`Lommerse
`
`Mooij
`
`Motherwell
`
`Price
`
`Scheraga
`
`Schweizer
`
`Schmidt
`
`van Eijck
`
`Verwer
`
`Williams
`
`P21/a
`P21/c
`P212121
`P(cid:22)1
`P21/c
`P21/c
`P(cid:22)1
`P21/c
`P21/c
`Pbca
`P(cid:22)1
`P(cid:22)1
`P(cid:22)1
`P21/a
`P212121
`P21/a
`P212121
`Pbca
`P21/c
`P21/c
`P21/c
`Pbca
`P212121
`P21
`Pbca
`P21/c
`P21/c
`Pbca
`P21/c
`Pbca
`P(cid:22)1
`P21/c
`P21/c
`C2/c
`P21/c
`Pbca
`P21/c
`P21/c
`P212121
`P21/c
`P21/n
`P21/c
`P21/c
`P21/c
`P21/c
`C2/c
`
`a (AÊ )
`
`7.704
`10.159
`7.623
`7.307
`8.900
`9.232
`5.667
`9.096
`10.065
`12.031
`6.949
`6.819
`6.892
`9.958
`11.538
`8.024
`8.091
`11.579
`6.567
`10.247
`9.229
`11.974
`8.037
`6.288
`11.748
`11.129
`6.144
`11.526
`10.112
`12.003
`9.976
`8.434
`6.199
`11.295
`10.087
`11.394
`9.284
`10.262
`11.232
`9.071
`9.132
`10.171
`6.226
`10.420
`6.370
`22.280
`
`b (AÊ )
`
`10.606
`7.927
`12.255
`5.835
`7.840
`8.550
`6.450
`8.146
`8.021
`11.527
`6.801
`5.937
`6.423
`7.596
`5.955
`10.509
`9.500
`11.785
`10.529
`7.706
`10.406
`11.366
`6.527
`7.926
`11.638
`6.142
`7.094
`11.859
`7.918
`11.196
`7.173
`6.543
`15.101
`12.271
`7.415
`11.696
`8.541
`7.537
`11.292
`7.843
`8.108
`7.990
`10.901
`7.480
`12.160
`10.290
`
`c (AÊ )
`
`9.338
`9.899
`8.341
`10.233
`13.047
`12.156
`10.918
`10.650
`10.146
`11.719
`8.124
`10.416
`10.368
`10.474
`11.346
`9.182
`9.998
`11.145
`12.407
`9.962
`7.963
`11.560
`14.097
`7.668
`11.152
`15.531
`18.148
`11.482
`9.697
`11.379
`5.707
`15.774
`10.352
`12.965
`9.793
`10.948
`11.721
`9.826
`5.916
`12.596
`10.662
`10.034
`12.482
`9.910
`10.180
`6.890
`
`(cid:11) ((cid:14))
`
`(cid:12) ((cid:14))
`
`90.0
`90.0
`90.0
`76.8
`90.0
`90.0
`86.8
`90.0
`90.0
`90.0
`87.4
`90.5
`77.2
`90.0
`90.0
`90.0
`90.0
`90.0
`90.0
`90.0
`90.0
`90.0
`90.0
`90.0
`90.0
`90.0
`90.0
`90.0
`90.0
`90.0
`109.9
`90.0
`90.0
`90.0
`90.0
`90.0
`90.0
`90.0
`90.0
`90.0
`90.0
`90.0
`90.0
`90.0
`90.0
`90.0
`
`95.0
`77.0
`90.0
`95.1
`126.1
`127.7
`81.7
`97.1
`104.8
`90.0
`89.5
`92.4
`82.8
`105.2
`90.0
`83.0
`90.0
`90.0
`77.4
`76.3
`83.9
`90.0
`90.0
`100.7
`90.0
`134.3
`87.4
`90.0
`77.0
`90.0
`104.1
`88.4
`116.9
`81.7
`103.6
`90.0
`128.1
`104.5
`90.0
`56.0
`97.0
`75.9
`76.8
`77.1
`102.0
`96.2
`
` ((cid:14))
`
`90.0
`90.0
`90.0
`111.5
`90.0
`90.0
`79.2
`90.0
`90.0
`90.0
`85.1
`62.8
`61.3
`90.0
`90.0
`90.0
`90.0
`90.0
`90.0
`90.0
`90.0
`90.0
`90.0
`90.0
`90.0
`90.0
`90.0
`90.0
`90.0
`90.0
`83.9
`90.0
`90.0
`90.0
`90.0
`90.0
`90.0
`90.0
`90.0
`90.0
`90.0
`90.0
`90.0
`90.0
`90.0
`90.0
`
`the experimental structure, and the higher RMSD is explained
`by the fact that the intramolecular force ®eld was unable to
`reproduce the correct puckering of the ®ve-membered ring.
`At the workshop discussion, it was decided that a more
`detailed comparison of submitted structures to the experi-
`mental structures would be of interest. Also those participants
`who had energy-ranked lists of structures (lowest energy is
`rank 1, next rank 2 etc.) were invited to contribute these to
`identify whether a match with the experimental structure
`could be found at a rank higher than 3. The comparison results
`for molecules IV, V and VI are given in Tables 6, 7 and 8,
`respectively, and these tables allow a comparison of how
`accurately the different force ®elds reproduced these struc-
`tures. The ab initio submissions are given ®rst in each table,
`followed by higher-ranked structures from the lists with
`
`energy differences from the lowest value. In some cases where
`the structure was not found in the energy list, authors have
`presented a `minimized experimental' (ME) structure, using
`their relevant force ®eld to test how well the force ®eld does
`describe this energy minimum. In these cases, the structure has
`no rank in the list, but the symbol ME is given.
`This detailed comparison of structures with the experi-
`mental reference was performed after the workshop by
`Dzyabchenko, using the program CRYCOM (Dzyabchenko,
`1994). The ®rst step was to bring each pair of structures (target
`and reference) to the same space-group setting whenever they
`were not the same. Atom connectivity matching was auto-
`matically carried out by the CSD program GEOM78. The
`rigid-body parameters (i.e. the centre of mass coordinates and
`the three Euler angles of both molecules) were calculated with
`
`652 Motherwell et al.
`
`(cid:15) Crystal structure prediction
`
`Acta Cryst. (2002). B58, 647±661
`
`Page 6 of 15
`
`

`
`Table 4
`Submitted results for molecule V.
`
`Results are presented in the space-group settings as submitted. Correct predictions are given in bold type. RMSD-Pack is calculated by the Lommerse method and
`is only given when a meaningful ®t could be found within a certain tolerance.
`
`research papers
`
`Name
`
`Space group
`
`Experimental
`Ammon
`
`Dzyabchenko
`
`Erk
`
`Gavezzotti
`
`Hofmann
`
`Leusen
`
`Lommerse
`
`Mooij
`
`Motherwell
`
`Price
`
`Scheraga
`
`Schmidt
`
`van Eijck²
`
`Verwer
`
`Williams³
`
`P212121
`P212121
`P212121
`P212121
`P212121
`P212121
`P212121
`P21
`P212121
`P212121
`P212121
`P21
`P212121
`P(cid:22)1
`P21/c
`P21/c
`P212121
`P212121
`P21
`P21
`P212121
`P21
`P212121
`P21
`P212121
`P212121
`P212121
`P21
`P212121
`P21
`P212121
`P21
`P212121
`P21
`P212121
`P212121
`P212121
`P212121
`P212121
`P212121
`P212121
`P212121
`P212121
`Cc
`P21
`P212121
`
`a (AÊ )
`
`7.2643
`10.394
`10.799
`10.595
`12.959
`7.906
`13.351
`8.04
`14.319
`7.463
`11.858
`6.9771
`11.720
`6.874
`10.876
`10.718
`7.336
`12.391
`7.158
`7.711
`9.486
`7.481
`13.144
`7.096
`10.746
`7.955
`7.602
`8.804
`16.223
`7.218
`10.859
`7.215
`9.967
`7.309
`8.920
`6.742
`7.277
`9.985
`7.949
`14.651
`7.178
`12.853
`11.171
`6.91
`8.12
`10.66
`
`b (AÊ )
`
`10.6393
`16.354
`12.802
`11.524
`10.44
`8.931
`8.524
`10.508
`11.008
`14.716
`7.015
`12.04
`9.638
`9.962
`9.285
`9.285
`12.11
`6.924
`10.485
`10.744
`11.243
`9.233
`7.228
`10.549
`9.982
`8.485
`14.106
`10.919
`10.413
`10.703
`12.907
`11.266
`11.528
`10.236
`9.214
`12.018
`8.708
`15.891
`11.386
`8.524
`13.323
`7.381
`10.679
`15.97
`10.81
`6.93
`
`c (AÊ )
`
`15.6331
`7.128
`8.608
`9.884
`8.36
`15.959
`10.083
`7.446
`7.571
`10.96
`13.178
`7.422
`10.058
`8.441
`15.602
`16.000
`13.343
`13.628
`8.247
`8.16
`11.584
`9.095
`11.939
`8.545
`10.848
`16.424
`10.353
`8.224
`7.177
`8.269
`8.562
`8.811
`10.76
`8.454
`13.332
`13.687
`17.461
`7.119
`12.397
`8.716
`12.216
`12.375
`10.013
`10.53
`6.95
`15.58
`
`(cid:11) ((cid:14))
`
`90
`90
`90
`90
`90
`90
`90
`90
`90
`90
`90
`90
`90
`95.5
`90
`90
`90
`90
`90
`90
`90
`90
`90
`90
`90
`90
`90
`90
`90
`90
`90
`90
`90
`90
`90
`90
`90
`90
`90
`90
`90
`90
`90
`90
`90
`90
`
`(cid:12) ((cid:14))
`
`90
`90
`90
`90
`90
`90
`90
`104.4
`90
`90
`90
`116.1
`90
`80.6
`49.9
`49.2
`90
`90
`76.1
`97.7
`90
`97.14
`90
`112.8
`90
`90
`90
`46.67
`90
`67.55
`90
`60.31
`90
`78
`90
`90
`90
`90
`90
`90
`90
`90
`90
`81.26
`70.28
`90
`
` ((cid:14))
`
`90
`90
`90
`90
`90
`90
`90
`90
`90
`90
`90
`90
`90
`100.3
`90
`90
`90
`90
`90
`90
`90
`90
`90
`90
`90
`90
`90
`90
`90
`90
`90
`90
`90
`90
`90
`90
`90
`90
`90
`90
`90
`90
`90
`90
`90
`90
`
`RMSD-Pack (AÊ )
`
`0.364
`
`0.347
`
`0.777
`
`0.263
`
`² van Eijck's result has the correct crystal packing, but a large RMSD owing to differences in molecular model conformation. The RMSD given was calculated by Dzyabchenko's
`program.
`³ Williams's submission in Cc is an error for this chiral molecule.
`
`reference to a de®ned set of molecular axes. These six para-
`meters together with the unit-cell parameters were used as the
`basis for comparison.
`The target structure (i.e. the prediction structure) was
`matched against the reference experimental structure with all
`equivalent descriptions (ED) of
`the former taken into
`account. These ED were generated from the original one by
`changing the direction and the origin of the unit-cell axes in all
`possible ways compatible with the given space group; these are
`given by the so-called af®ne normalizer group derivative for
`the space group. Whenever assignment of local axes allowed
`ambiguity because of molecular symmetry (as in compound
`
`IV), the list of ED was further expanded by virtue of the point-
`group operations.
`For the ¯exible molecule VI, the comparison involved
`consideration of sets of rigid-body parameters of
`three
`constituent fragments: SO2, the phenyl and the remaining
`hetero-N-aromatic group. Each fragment was treated inde-
`pendently as if it were a single rigid molecule, with its parti-
`cular point-group symmetry taken into account and with a
`common condition that the cell transformation and origin shift
`are the same.
`As a result of this rigid-body treatment, the deviations in
`the cell dimensions, the net centre of mass translation and the
`
`Acta Cryst. (2002). B58, 647±661
`
`Motherwell et al.
`
`(cid:15) Crystal structure prediction 653
`
`Page 7 of 15
`
`

`
`research papers
`
`Table 5
`Submitted results for molecule VI.
`
`Results are presented in the space-group settings as submitted. There were no correct predictions. RMSD-Pack is calculated by the Lommerse method and is only
`given when a meaningful ®t could be found within a certain tolerance.
`
`Name
`
`Space group
`
`Experimental
`Ammon
`
`Dzyabchenko
`
`Erk
`
`Hofmann
`
`Leusen
`
`Mooij
`
`Scheraga
`
`Schmidt
`
`van Eijck
`
`Verwer
`
`Williams
`
`P21/c
`P(cid:22)1
`P21/c
`P21/c
`Pbca
`Pbca
`Pbca
`C2c
`C2c
`P21/c
`P(cid:22)1
`P(cid:22)1
`P21/c
`P21/a
`P21/a
`P21/c
`P(cid:22)1
`P21/c
`Pbca
`P21/c
`P21/c
`P21/c
`C2/c
`P(cid:22)1
`P21/c
`P(cid:22)1
`P(cid:22)1
`P21/c
`P21/a
`An
`Pbca
`P21/c
`P21/c
`Pbca
`
`a (AÊ )
`
`8.2506
`11.508
`7.551
`7.739
`10.862
`9.317
`9.351
`12.634
`16.505
`9.369
`10.886
`5.385
`10.743
`15.941
`11.893
`8.086
`10.663
`14.106
`23.316
`9.008
`7.656
`7.921
`22.866
`6.852
`4.946
`9.847
`9.338
`13.021
`7.010
`7.054
`24.384
`13.31
`14.06
`7.83
`
`b (AÊ )
`
`8.9643
`6.676
`23.099
`6.683
`8.379
`9.85
`10.345
`7.6702
`10.896
`16.983
`7.632
`11.543
`15.792
`8.976
`13.649
`8.674
`8.738
`5.895
`8.798
`12.857
`11.14
`14.937
`5.533
`7.775
`9.306
`30.491
`16.234
`7.681
`24.520
`24.541
`7.134
`12.03
`11.73
`11.99
`
`c (AÊ )
`
`15.087
`7.614
`6.794
`22.817
`23.845
`24.697
`22.923
`24.832
`14.139
`7.932
`8.062
`10.84
`7.107
`7.801
`7.569
`16.118
`9.473
`16.626
`10.753
`15.817
`17.797
`11.197
`16.734
`11.157
`23.119
`21.458
`8.379
`11.940
`6.657
`6.602
`13.281
`7.15
`6.98
`23.96
`
`(cid:11) ((cid:14))
`
`90
`85.9
`90
`90
`90
`90
`90
`90
`90
`90
`120.8
`69.8
`90
`90
`90
`90
`92.3
`90
`90
`90
`90
`90
`90
`83.7
`90
`4.87
`34.45
`90
`90
`90
`90
`90
`90
`90
`
`(cid:12) ((cid:14))
`
`91.21
`95.3
`82.5
`82.9
`90
`90
`90
`81.0
`62.5
`70.1
`93.9
`65.2
`111.9
`86.0
`114.0
`98.0
`55.7
`126.1
`90
`133.51
`118.81
`101.27
`91.3
`73.6
`96.5
`90.49
`94.10
`62.98
`85.2
`93.8
`90
`101.26
`76.54
`90
`
` ((cid:14))
`
`RMSD-Pack (AÊ )
`
`90
`81.2
`90
`90
`90
`90
`90
`90
`90
`90
`97.6
`3.6
`90
`90
`90
`90
`60.2
`90
`90
`90
`90
`90
`90
`69.9
`90
`90.51
`71.97
`90
`90
`90
`90
`90
`90
`90
`
`net rotation angle of the molecule (or each of the rigid frag-
`ments in molecule VI) were determined.
`In addition, an alternative method of comparison was
`performed in an atom±atom matching mode, where each atom
`of the molecule was formally treated as an independent
`fragment, with rotation ignored. This automatically resulted in
`fully standardized lists of coordinates where respective atom