PLATON and STRUCTURE VALIDATION

1
PLATON and STRUCTURE VALIDATION

• Ton Spek
• National Single Crystal
• Service Facility,
• Utrecht University,
• The Netherlands.
• Goettingen, 13-Oct-2007

2
Overview of the Talk

• What is PLATON
• Structure Validation
• Concluding Remarks
• Copy http//cryst.chem.uu.nl

3
What is PLATON

• PLATON is a collection of tools for single
  crystal structure analysis bundled within a
  single SHELX compatible program.
• The tools are either extended versions of
  existing tools or unique to the program.
• The program was/is developed over of period of
  more than 25 years in the context of our National
  Single Crystal Service Facility in the
  Netherlands.

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PLATON USAGE

• Today, PLATON is most widely used implicitly in
  its validation incarnation for all single crystal
  structures that are validated with the IUCr
  CHECKCIF utility.
• Tools are available in PLATON to analyze and
  solve the reported issues that need attention.

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OTHER PLATON USAGE

• PLATON also offers guided/automatic structure
  determination and refinement tools for routine
  structure analyses from scratch (i.e. the
  Unix-only SYSTEM S tool and the new
  FLIPPER/STRUCTURE tool that is based on the
  Charge Flipping Ab initio phasing method).
• Next Slide Main Function Menu ?

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Selected Tools

• ADDSYM Detection and Handling of Missed
  (Pseudo)Symmetry
• TwinRotMat Detection of Twinning
• SOLV Report of Solvent Accessible Voids
• SQUEEZE Handling of Disordered Solvents in
  Least Squares Refinement (Easy to use Alternative
  for Clever Disorder Modelling)
• BijvoetPair Post-refinement Absolute Structure
  Determination (Alternative for Flack x)
• VALIDATION PART of IUCr CHECKCIF

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ADDSYM

• Often, a structure solves only in a space group
  with lower symmetry than the correct space group.
  The structure should subsequently be checked for
  higher symmetry.
• About 1 of the 2006 2007 entries in the CSD
  need a change of space group.
• E.g. A structure solves only in P1. ADDSYM is a
  tool to come up with the proper space group and
  to carry out the transformation (? new .res)
• Next slide Recent example of missed symmetry

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Organic Letters (2006) 8, 3175
Correct Symmetry ?
P1, Z 8
CCo
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Test for Higher Symmetry

• Start PLATON with a .ins or .cif
• Click on ADDSYM on the main menu
• Analyse automatically generated result
• ? Display next

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After Transformation to P212121, Z 2
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(Pseudo)Merohedral Twinning

• Options to handle twinning in L.S. refinement
  available in SHELXL, CRYSTALS etc.
• Problem Determination of the Twin Law that is in
  effect.
• Partial solution coset decomposition, try all
  possibilities
• (I.e. all symmetry operations of the lattice
  but not of the structure)
• ROTAX (S.Parson et al. (2002) J. Appl. Cryst.,
  35, 168.
• (Based on the analysis of poorly fitting
  reflections of the type F(obs) gtgt F(calc) )
• TwinRotMat Automatic Twinning Analysis as
  implemented in PLATON (Based on a similar
  analysis but implemented differently)

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TwinRotMat Example

• Originally published as disordered in P3.
• Solution and Refinement in the trigonal space
  group P-3 ?R 20.
• Run PLATON/TwinRotMat on CIF/FCF
• Result Twin law with an the estimate of the
  twinning fraction and the estimated drop in
  R-value
• Example of a Merohedral Twin ?

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Ideas behind the Algorithm

• Reflections effected by twinning show-up in the
  least-squares refinement with F(obs) gtgt F(calc)
• Overlapping reflections necessarily have the same
  Theta value within a tolerance.
• Generate a list of implied possible twin axes
  based on the above observations.
• Test each proposed twin law for its effect on R.

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Possible Twin Axis
H H H
Candidate twinning axis (Normalize !)
H
H
Reflection with F(obs) gtgt F(calc)
Strong reflection H with theta close to theta of
reflection H
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Solvent Accessible Voids

• A typical crystal structure has only in the order
  of 65 of the available space filled.
• The remainder volume is in voids (cusps)
  in-between atoms (too small to accommodate an
  H-atom)
• Solvent accessible voids can be defined as
  regions in the structure that can accommodate at
  least a sphere with radius 1.2 Angstrom without
  intersecting with any of the van der Waals
  spheres assigned to each atom in the structure.
• Next Slide Void Algorithm Cartoon Style ?

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DEFINE SOLVENT ACCESSIBLE VOID
STEP 1 EXCLUDE VOLUME INSIDE THE VAN DER
WAALS SPHERE
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DEFINE SOLVENT ACCESSIBLE VOID
STEP 2 EXCLUDE AN ACCESS RADIAL VOLUME TO
FIND THE LOCATION OF ATOMS WITH THEIR CENTRE AT
LEAST 1.2 ANGSTROM AWAY
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DEFINE SOLVENT ACCESSIBLE VOID
STEP 3 EXTEND INNER VOLUME WITH POINTS
WITHIN 1.2 ANGSTROM FROM ITS OUTER BOUNDS
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Listing of all voids in the triclinic unit cell
Cg
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VOID APPLICATIONS

• Calculation of Kitaigorodskii Packing Index
• As part of the SQUEEZE routine to handle the
  contribution of disordered solvents in crystal
  structure refinement
• Determination of the available space in solid
  state reactions (Ohashi)
• Determination of pore volumes, pore shapes and
  migration paths in microporous crystals

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SQUEEZE

• Takes the contribution of disordered solvents to
  the calculated structure factors into account by
  back-Fourier transformation of density found in
  the solvent accessible volume outside the
  ordered part of the structure (iterated).
• Filter Input shelxl.res shelxl.hkl
• Output solvent free shelxl.hkl
• Refine with SHELXL or Crystals
• NoteSHELXL lacks option for fixed contribution
  to Structure Factor Calculation.

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SQUEEZE Algorithm

• Calculate difference map (FFT)
• Use the VOID-map as a mask on the FFT-map to set
  all density outside the VOIDs to zero.
• FFT-1 this masked Difference map -gt contribution
  of the disordered solvent to the structure
  factors
• Calculate an improved difference map with F(obs)
  phases based on F(calc) including the recovered
  solvent contribution and F(calc) without the
  solvent contribution.
• Recycle to 2 until convergence.

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SQUEEZE In the Complex Plane
Fc(solvent)
Fc(total)
Fc(model)
Fobs
Solvent Free Fobs
Black Split Fc into a discrete and solvent
contribution Red For SHELX refinement,
temporarily substract recovered solvent
contribution from Fobs.
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Comment

• The Void-map can also be used to count the number
  of electrons in the masked volume.
• A complete dataset is required for this feature.
• Ideally, the solvent contribution is taken into
  account as a fixed contribution in the Structure
  Factor calculation (CRYSTALS) otherwise it is
  substracted temporarily from F(obs)2 (SHELXL)
  and re-instated afterwards with info saved beyond
  column 80 for the final Fo/Fc list.

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Publication Note

• Always give the details of the use of SQUEEZE in
  the comment section
• Append the small CIF file produced by PLATON to
  the main CIF
• Use essentially complete data sets with
  sufficient resolution only.
• Make sure that there is no unresolved charge
  balance problem.

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Post-Refinement Absolute Structure Determination

• Generally done as part of the least squares
  refinement with a twinning parameter.(Flack x)
• Determine Flack x parameter su
• Validity Analysis following the Flack
  Bernardinelli criteria.
• Often indeterminate conclusions obtained in the
  case of light atom structures
• Alternative approaches offered by PLATON ?

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Scatter Plot of Bijvoet Differences

• Plot of the Observed Bijvoet Differences against
  the Calculated Differences.
• A Least-Squares line is calculated
• The Green least squares line should run from the
  lower left to the upper right corner for the
  correct absolute structure.
• Vertical bars on data points indicate the su
• on the Bijvoet Difference. Example ?

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Excellent Correlation
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Practical Aspects of Flack x

• The structure should contain atoms with
  sufficiently strong anomalous dispersion
  contributions for the radiation used (generally
  MoKa) in the experiment (e.g. Br).
• Preferably, but not nesessarily, a full set of
  Friedel pairs is needed. (danger correlation !)
• Unfortunately, many relevant pharmaceuticals
  contain in their native form only light atoms
  that at best have only weak anomalous scattering
  power and thus fail the strict Flack conditions.

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Light Atom Targets

• Options for the Absolute Structure
  Determination of Light Atom Compounds
• Add HBr in case of tertiary N.
• Co-crystallize with e.g. CBr4.
• Co-crystallize with compound with known. absolute
  configuration.
• Alternative Statistical analysis of Bijvoet pair
  differences.

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Statistical Analysis of Bijvoet Pairs

• Many experimentalists have the feeling that the
  official Flack x method is too conservative.
• This Experience is based on multiple carefully
  executed experiments with compounds with known
  absolute structure.
• The feeling is that also in light atom structures
  the average of thousands of small Bijvoet
  differences will point in the direction of the
  correct enantiomorph.
• Example The Nonius CAD4 test crystal ?

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MoKa, P212121
Example Ammonium Bitartrate Test
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Ammonium BiTartrate (MoKa)
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Bayesian Approach

• Rob Hooft (Bruker) has developed an alternative
  approach for the analyses of Bijvoet differences
  that is based on Bayesian statistics. (Paper
  under review)
• Under the assumption that the material is
  enantiopure, the probability that the assumed
  absolute structure is correct, given the set of
  observed Bijvoet Pair Differences, is calculated.
• An extension of the method also offers the Fleq y
  (Hooft y) parameter to be compared with the Flack
  x.
• Example Ascorbic Acid, P21, MoKa data ?

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MoKa
Natural Vitamin C, L-()Ascorbic Acid
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L-() Ascorbic Acid
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Hooft y Proper Procedure

• Collect data with an essentially complete set of
  Bijvoet Pairs
• Refine in the usual way (preferably) with BASF
  and TWIN instructions (SHELXL)
• Structure Factors to be used in the analysis are
  recalculated in PLATON from the parameters in the
  CIF (No Flack x contribution).

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Do we need Validation ?Some Statistics

• Validation CSD Entries 2006 2007
• Number of entries 35760
• of likely Space Group Changes 384
• of structures with voids 3354
• Numerous problems with H, O, OH, H2O etc.

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Structure Validation

• Some Examples of Recently Published Structures
  with a Problem that Apparently Escaped the
  Attention of the Referees.
• Promote CheckCif as the Current (Partial) IUCr
  Solution to this problem.
• Details of what PLATON can do in this Context.
• Next An Example of a strange structure in the
  CSD ?

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Structure of an Interesting CH3 Bridged Zr Dimer
Paper has been cited 47 times !
So can we believe this structure?
The Referees did !
But
H .. H 1.32 Ang. !
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Comment

• The methyl hydrogen atoms are expected outside
  the Zr2C2 ring (and indeed have been found in
  similar structures)
• Referees likely had no access to (or did not
  access) the primary data other than the ORTEP
  illustration in the paper.
• General problem A limited number of experts is
  available to referee too many structural papers
  that offer only limited primary (deposited) data.

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Dalton Trans. (2001), 729-735
Next Slide ORTEP with downloaded CIF data ?
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From CSD
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Organometallics (2006) 25, 1511-1516
Next Slide This is why the reported density is
low and the R and Rw high ?
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Solvent Accessible Void of 235 Ang3 out
of 1123 Ang3
Not Accounted for in the Refinement Model
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SOLUTION

• A solution for the structure validation
  problem was pioneered by the International Union
  of Crystallography
• Provide and archive crystallographic data in the
  computer readable CIF standard format.
• Offer Automated validation, with a computer
  generated report for authors and referees.
• Have journals enforce a structure validation
  protocol.
• - The IUCr journals and most major journals now
  indeed implement some form of validation
  procedure.

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THE CIF DATA STANDARD

• Driving Force Syd Hall (IUCr/ Acta Cryst C)
• Early Adopted by XTAL SHELX(T)L.
• Currently WinGX,Crystals,Texsan, Maxus etc.
• Acta Cryst. C/E Electronic Submission
• Acta Cryst.Automatic Validation at the Gate
• CIF data available for referees for detailed
  inspection (and optional calculations).
• Data retrieval from the WEB for published papers
• CCDC Deposition in CIF-FORMAT.

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VALIDATION QUESTIONS

• Single crystal validation addresses three
• simple but important questions
• 1 Is the reported information complete?
• 2 What is the quality of the analysis?
• 3 Is the Structure Correct?

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IUCr CHECKCIF WEB-Service

• http//checkcif.iucr.org reports the outcome of
• IUCr standard tests
• Consistency, Missing Data, Proper Procedure,
  Quality etc.
• Additional PLATON based tests
• Missed Symmetry, Twinning, Voids, Geometry,
  Displacement Parameters, Absolute Structure etc.

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ALERT LEVELS

• ALERT A Serious Problem
• ALERT B Potentially Serious Problem
• ALERT C Check Explain
• ALERT G Verify or Take Notice

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ALERT TYPES

• 1 - CIF Construction/Syntax errors,
• Missing or Inconsistent Data.
• 2 - Indicators that the Structure Model
• may be Wrong or Deficient.
• 3 - Indicators that the quality of the results
• may be low.
• 4 - Cosmetic Improvements, Queries and
• Suggestions.

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In-House Validation with PLATON

• Details www.cryst.chem.uu.nl/platon
• Available for UNIX/LINUX, Windows, Mac-OSX
• Driven by the file CHECK.DEF with criteria, ALERT
  messages and advice.
• Unix platon u structure.cif
• Result on file structure.chk
• Applicable on CIFs and CCDC-FDAT

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EXAMPLE OF PLATON GENERATED ALERTS FOR A
RECENT PAPER PUBLISHED IN J.Amer.Chem.Soc. (2007)
Attracted special attention in Chemical and
Engineering News
Properly Validated ?
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Problems Addressed by PLATON/CIF-CHECK

• Missed Higher Space Group Symmetry
• Solvent Accessible Voids in the Structure
• Unusual Displacement Parameters
• Hirshfeld Rigid Bond test
• Misassigned Atom Type
• Population/Occupancy Parameters
• Mono Coordinated/Bonded Metals
• Isolated Atoms (e.g. O, H, Transition Metals)

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More Problems Addressed by PLATON

• Too Many Hydrogen Atoms on an Atom
• Missing Hydrogen Atoms
• Valence Hybridization
• Short Intra/Inter-Molecular Contacts
• O-H without Acceptor
• Unusual Bond Length/Angle
• CH3 Moiety Geometry
• To be extended with tests for new problems
  invented by authors.

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Additional Problems Addressed byPLATON/FCF-CHECK

• Information from .cif and .fcf files
• Report on the resolution of the data
• Report about randomly missing data
• Check the completeness of the data (e.g. for
  missing cusps of data
• Report on Missed (Pseudo) Merohedral Twinning
• Report on Friedel Pairs and Absolute Structure
• Next Slide ASYM VIEW Display for the inspection
  of the data completeness ?

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Section in reciprocal space
Missing cusp of data
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The Missed Symmetry Problem

• Up to 10 of the structures in space groups such
  as Cc have higher symmetry (e.g. C2/c, R-3c, Fdd2
  etc.) than was originally reported.
• (To be Marshed is not good for your scientific
  reputation as a crystallographer).
• MISSYM (Y. LePage) PLATON/ADDSYM algorithm
  addresses the problem.
• - Next Slide Example ?

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Organometallics (2004) 23,2310
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Change of Space Group ALERT
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Things to be Checked when ADDSYM suggests a new
Space Group

• Consistency of the new cell parameters with the
  new crystal system (90.2 90 ?)
• Proposed new symmetry consistent with the
  reflection data ?
• Analyse the new implied systematic absences
• Case of Pseudo-symmetry ?
• Analyze potential disorder (real/artifact)
• Successful re-refinement

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Incorrectly Oriented O-H

• The O-H moiety is generally, with very few
  exceptions, part of a D-H..A system.
• An investigation of structures in the CSD brings
  up many exceptions.
• Closer analysis shows that misplacement of the
  O-H hydrogen atom is in general the cause.
• Molecules have an environment in the crystal !
• Example ?

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Example of a PLATON/Check Validation Report Two
ALERTS related to the misplaced Hydrogen Atom
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Validation Looks at inter-molecular contacts
Unsatisfactory Hydrogen Bond Network
Correct !
ALERT !
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Wrong Structures

• Sometimes (semi) automatic structure
  determination procedures can come up with
  reasonably looking but wrong structures.
• Structure validation software should send out
  proper ALERTS to the investigators
• (e.g. IUCr Checkcif)

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Structure Determination Artifacts

• Pseudo-symmetry easily results in false
  structures (often requiring a disorder model).
• Example An Organometallic-AuCl compound from the
  CSD with the Cl in the
• wrong position ? Very Short C-H..Cl ?!
• ALERTED by validation (C..Cl 2.19 Ang)
• Moving Cl to the correct position drops
• R from 4 to 2 (? see next two slides).

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Consult the CSD

• It is a good idea to always consult the CSD for
  previous reports on structures related to the one
  at hand (in particular when the result looks
  unique).
• The statistics provided by VISTA (CCDC) can be
  very helpful for this.
• However, be aware, such an analysis often shows
  outliers. Many of those appear to be errors.
• Example A search for short S..S contacts gave

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Entry from the CSD
S
H
76
But with Space Group Symmetry
gt Different structure with S-S Bond !
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THE MESSAGE

• Validation should not be postponed to the
  publication phase. All validation issues should
  be taken care of during the analysis.
• Everything unusual in a structure is suspect,
• mostly incorrect (artifact) and should be
  investigated and discussed in great detail and
  supported by additional independent evidence.
• - The CSD can be very helpful when looking for
  possible precedents (but be careful ?)

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CONCLUSION

• Validation Procedures are excellent Tools to
• Set Quality Standards (Not just on R-Value)
• Save a lot of Time in Checking, both by the
  Investigators and the Journals (referees)
• - Point at Interesting Features
  (Pseudo-Symmetry,
• short Interactions etc.) to be discussed.
• Surface a problem that only an experienced
  Crystallographer might be able to Address
• Proof of a GOOD structure.

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Additional Info

• http//www.cryst.chem.uu.nl
• (including a copy of this powerpoint
  presentation)
• Thanks
• for your attention !!

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