.. highlight:: console

Gemmi program
#############

The library comes with a command-line program which is also named gemmi;
running a program is easier than calling a library function.

This program is actually a set of small programs, each of them
corresponding to a subcommand:

.. literalinclude:: gemmi-help.txt
   :language: console

validate
========

A CIF validator. Apart from checking the syntax it can check most of the rules
imposed by DDL1 and DDL2 dictionaries.

.. literalinclude:: validate-help.txt
   :language: console

.. _grep:

grep
====

Searches for a specified tag in CIF files and prints the associated values,
one value per line::

  $ gemmi grep _refine.ls_R_factor_R_free 5fyi.cif.gz
  5FYI:0.2358
  $ gemmi grep _refine.ls_R_factor_R_free mmCIF/mo/?moo.cif.gz
  1MOO:0.177
  3MOO:0.21283
  4MOO:0.22371
  5MOO:0.1596
  5MOO:0.1848
  $ gemmi grep -b _software.name 5fyi.cif.gz
  DIMPLE
  PHENIX

Some of the command-line options correspond to the options of GNU grep
(``-c``, ``-l``, ``-H``, ``-n``).
As with other utilities, option ``--help`` shows the usage:

.. literalinclude:: grep-help.txt
   :language: console

This is a minimalistic program designed to be used together with Unix
text-processing utilities. For example, it cannot filter values itself,
but one may use grep::

  $ gemmi grep _pdbx_database_related.db_name /pdb/mmCIF/aa/* | grep EMDB
  4AAS:EMDB
  5AA0:EMDB

Gemmi-grep tries to be simple to use like Unix grep, but at the same time
it is aware of the CIF syntax rules. In particular, ``gemmi grep _one``
will give the same output for both ``_one 1`` and ``loop_ _one _two 1 2``.
This is helpful in surprising corner cases. For example, when a PDB entry
has two Rfree values (see the 5MOO example above).

Gemmi-grep does not support regular expression, only globbing (wildcards):
``?`` represents any single character, ``*`` represents any number of
characters (including zero). When using wildcards you may also want
to use the ``-t`` option which prints the tag::

  $ gemmi grep -t _*free 3gem.cif
  3GEM:[_refine.ls_R_factor_R_free] 0.182
  3GEM:[_refine.ls_percent_reflns_R_free] 5.000
  3GEM:[_refine.ls_number_reflns_R_free] 3951
  3GEM:[_refine.correlation_coeff_Fo_to_Fc_free] 0.952
  3GEM:[_refine_ls_shell.R_factor_R_free] 0.272
  3GEM:[_refine_ls_shell.number_reflns_R_free] 253

Let say we want to find extreme unit cell angles in the PDB.
``_cell.angle_*a`` will match _cell.angle_alpha as well as beta and gamma,
but not _cell.angle_alpha_esd etc.

::

  $ gemmi grep -d' ' _cell.angle_*a /pdb/mmCIF/ | awk '$2 < 50 || $2 > 140 { print $0; }'
  4AL2 144.28
  2EX3 45.40
  2GMV 145.09
  4NX1 140.060
  4OVP 140.070
  1SPG 141.90
  2W1I 146.58

The option ``-O`` is used to make gemmi-grep faster.
With this option the program finds only the first occurrence of the tag
in file. Note that if the file has only one block (like mmCIF coordinate
files) and the tag is specified without wildcards then we cannot have
more than one match anyway.

Searching the whole compressed mmCIF archive from the PDB
(35GB of gzipped files) should take on an average computer
between 10 and 30 minutes, depending where the searched tag is located.
This is much faster than with other CIF parsers (to my best knowledge)
and it makes the program useful for ad-hoc PDB statistics::

  $ gemmi grep -O -b _entity_poly.type /pdb/mmCIF | sort | uniq -c
        1 cyclic-pseudo-peptide
        4 other
        2 peptide nucleic acid
     9905 polydeoxyribonucleotide
      156 polydeoxyribonucleotide/polyribonucleotide hybrid
       57 polypeptide(D)
   168923 polypeptide(L)
     4559 polyribonucleotide
       18 polysaccharide(D)

Option ``-c`` counts the values in each block or file. As an example
we may check which entries have the biggest variety of chemical components
(spoiler: ribosomes)::

  $ gemmi grep -O -c _chem_comp.id /pdb/mmCIF | sort -t: -k2 -nr | head
  5J91:58
  5J8A:58
  5J7L:58
  5J5B:58
  4YBB:58
  5JC9:57
  5J88:57
  5IT8:57
  5IQR:50
  5AFI:50

Going back to moo, we may want to know to what experimental method
the Rfree values correspond::

  $ gemmi grep _refine.ls_R_factor_R_free -a _refine.pdbx_refine_id mmCIF/mo/?moo.cif.gz
  1MOO:0.177;X-RAY DIFFRACTION
  3MOO:0.21283;X-RAY DIFFRACTION
  4MOO:0.22371;X-RAY DIFFRACTION
  5MOO:0.1596;X-RAY DIFFRACTION
  5MOO:0.1848;NEUTRON DIFFRACTION

Option ``-a`` (``--and``) can be specified many times.
If we would add ``-a _pdbx_database_status.recvd_initial_deposition_date``
we would get the deposition date in each line. In this case it would be
repeated for 5MOO::

    5MOO:0.1596;X-RAY DIFFRACTION;2016-12-14
    5MOO:0.1848;NEUTRON DIFFRACTION;2016-12-14

To output TSV (tab-separated values) add ``--delimiter='\t'``.
What are the heaviest chains?

::

  $ gemmi grep --delimiter='\t' _entity.formula_weight -a _entity.pdbx_description /hdd/mmCIF/ | sort -nrk2 | head -3
  6EK0    1641906.750     28S ribosomal RNA
  5T2C    1640238.125     28S rRNA
  5LKS    1640238.125     28S ribosomal RNA

With some further processing the option ``-a`` can be used to generate
quite sophisticated reports. Here is a little demo:
https://project-gemmi.github.io/pdb-stats/

The major limitation here is that gemmi-grep cannot match
corresponding values from different tables (it is not possible
on the syntax level).
In the example above we have two values from the same table (``_refine``)
and a deposition date (single value). This works well.
But we are not able to add corresponding wavelengths from ``_diffrn_source``.
If an extra tag (specified with ``-a``) is not in the same table
as the main tag, gemmi-grep uses only the first value for this tag.

Unless we just count the number of value. Counting works for any combination
of tags::

  $ gemmi grep -c _refln.intensity_meas -a _diffrn_refln.intensity_net r5paysf.ent.gz
  r5paysf:63611;0
  r5payAsf:0;356684

(The file used in this example is structure factor (SF) mmCIF.
Strangely these files in the PDB have extension ``ent`` not ``cif``.)

The first number in the output above is the number of specified intensities.
If you would like to count in also values ``?`` and ``.`` specify
the option ``--raw``::

  $ gemmi grep --raw -c _refln.intensity_meas r5paysf.ent.gz
  r5paysf:63954
  r5payAsf:0

Gemmi-grep can work with any CIF files but it has one feature
specific to the PDB data. When :ref:`$PDB_DIR <pdb_dir>` is set
one may use PDB codes: just ``5moo`` or ``5MOO`` instead of the path
to ``5moo.cif.gz``. And for convenience, using a PDB code implies
option ``-O``.

The file paths or PDB codes can be read from a file.
For example, if we want to analyse PDB data deposited in 2016
we may first make a file that lists all such files::

  $ gemmi grep -H -O _pdbx_database_status.recvd_initial_deposition_date $PDB_DIR/structures/divided/mmCIF | \
          grep 2016 >year2016.txt

The 2016.txt file file has lines that start with the filename::

  /hdd/structures/divided/mmCIF/ww/5ww9.cif.gz:5WW9:2016-12-31
  /hdd/structures/divided/mmCIF/ww/5wwc.cif.gz:5WWC:2016-12-31

and a command such as::

  $ gemmi grep -f year2016.out _diffrn.ambient_temp

will grep only the listed cif files.

Exit status of gemmi-grep has the same meaning as in GNU grep:
0 if a line is selected, 1 if no lines were selected,
and 2 if an error occurred.

Examples
--------

comp_id check
~~~~~~~~~~~~~

The monomer library (Refmac dictionary) has tags such as
``_chem_comp_atom.comp_id``, ``_chem_comp_bond.comp_id`` that are expected
to be consistent with the block name::

  $ gemmi grep _*.comp_id $CLIBD_MON/a/ASN.cif
  comp_ASN:ASN
  [repeated 106 times]

We can quickly check if the names are always consistent by filtering
the output above with awk, for all monomer files, to print only lines
where the block name and comp_id differ::

  $ gemmi grep _*.comp_id $CLIBD_MON/? | awk -F: 'substr($1, 6) != $2'
  comp_M43:N09
  ...

planarity
~~~~~~~~~

The monomer library includes planarity restraints.
Each row in the ``_chem_comp_plane_atom`` table with the same ``plane_id``
represents atom belonging to the same plane.
What is the maximum number of atoms in one plane?

::

  $ gemmi grep _chem_comp_plane_atom.plane_id $CLIBD_MON/? | uniq -c | sort -nr | head -3
   38 comp_LG8:plan-1
   36 comp_UCM:plan-1
   36 comp_SA3:plan-1


.. _json:

cif2json
========

Syntax-level conversion from CIF 1.1 to JSON.
The JSON representation of the CIF data can be customized.
In particular we support CIF-JSON_ standard from COMCIFS
and mmJSON_ standard from PDBj (the latter is specific to mmCIF files).

.. literalinclude:: cif2json-help.txt
   :language: console

The major difference between the two is that CIF-JSON is dictionary-agnostic:
it cannot recognize categories (mmJSON groups by categories),
and it cannot recognize numbers (so it quotes the numbers).
CIF-JSON adds also two extra objects: "CIF-JSON" and "Metadata".
The minor differences are:

 =========== =========== ===========
    CIF        CIF-JSON    mmJSON
 =========== =========== ===========
  data_a      a           data_a
  _tag        _tag        tag
  _CasE       _case       CasE
  .           false       null
  ?           null        null
 =========== =========== ===========

.. _CIF-JSON: http://comcifs.github.io/cif-json
.. _mmJSON: https://pdbj.org/help/mmjson?lang=en


json2cif
========

The opposite of cif2json, but currently the only supported input is mmJSON.

.. literalinclude:: json2cif-help.txt
   :language: console

.. _convert:

convert
=======

Conversion between macromolecular coordinate formats: PDB, mmCIF and mmJSON.

.. literalinclude:: convert-help.txt
   :language: console

The PDB records written by Gemmi are formatted in the same way as in the wwPDB.
This makes possible to use ``diff`` to compare a PDB file from wwPDB
and a file converted by Gemmi from mmCIF. The file from wwPDB will have
more records, but the diff should still be readable.

The option ``--expand-ncs`` expands strict NCS, defined in
the ``MTRIX`` record (PDB) or in the ``_struct_ncs_oper`` table (mmCIF).
It is not obvious how to name the new chains that are added.
We have two options: either new names are generated (``=new``) or
the chain names are not changed but distinct segment IDs are added (``=dup``).

tags
====

Lists tags from one or multiple CIF files together with some statistics.

.. literalinclude:: tags-help.txt
   :language: console

By default, the tag statistics show in how many blocks the tag is present,
and the total number of non-null values for the tag:

.. code-block:: console

  $ gemmi tags components.cif.gz
  tag	block-count	value-count
  _chem_comp.formula	29748	29748
  _chem_comp.formula_weight	29749	29749
  ...
  _pdbx_chem_comp_identifier.type	29338	52899
  Tag count: 67
  Block count: 29749
  File count: 1

This program is run with option ``--full``
on the whole PDB archive to produce data for
`pdb-stats/tags.html <https://project-gemmi.github.io/pdb-stats/tags.html>`_.


map
===

Shows a summary of a CCP4 map file, optionally performing simple
transformations.

It plots a histogram of values in the console.
All histograms plotted by gemmi have a default width of 80 characters,
which can be overridden by the environment variable COLUMNS.
In Bash shell this variable is set automatically, but you need
``export COLUMNS`` to pass it to the program.

.. literalinclude:: map-help.txt
   :language: console


mask
====

Makes a mask in the CCP4 format. It has two functions:

* masking atoms if the input file is a coordinate file,
* using a threshold to convert a CCP4 map file to a mask file.

.. literalinclude:: mask-help.txt
   :language: console

mtz
===

.. literalinclude:: mtz-help.txt
   :language: console

.. _mtz2cif:

mtz2cif
=======

Converts reflection data from MTZ to mmCIF.

.. literalinclude:: mtz2cif-help.txt
   :language: console

.. _cif2mtz:

cif2mtz
=======

Converts reflection data from mmCIF to MTZ.

.. literalinclude:: cif2mtz-help.txt
   :language: console

Similarly to mtz2cif, this converter can also be customized using *spec files*.
The default spec files can be generated using options
``--print-spec`` for merged data and ``--print-spec --unmerged`` for unmerged.

.. literalinclude:: cif2mtz-spec.txt
   :language: none

.. _sf2map:

sf2map
======

Transforms map coefficients from either MTZ or SF mmCIF to CCP4 map.

.. literalinclude:: sf2map-help.txt
   :language: console

The ``--sample`` option is named after the ``GRID SAMPLE`` keyword of
the venerable CCP4 FFT program; its value has the same meaning.

map2sf
======

Transforms CCP4 map into map coefficients.

.. literalinclude:: map2sf-help.txt
   :language: console

merge
=====

Merge intensities from multi-record reflection file.

.. literalinclude:: merge-help.txt
   :language: console

.. _sfcalc:

sfcalc
======

Calculates structure factors from a model.

.. literalinclude:: sfcalc-help.txt
   :language: console

In general, structure factors can be calculated

* either directly, by summing contributions from each atom to each reflection,
* or by calculating an electron density on a grid and using discrete
  Fourier transform.

This program can measure the errors resulting from the latter method
(in addition to its main function -- calculation of the structure factors).
The errors depend on

* the grid spacing -- controlled by the oversampling ``--rate=R``;
  the maximum spacing is *d*\ :sub:`min`/2\ *R*,
* atomic radius -- we neglect electron density of the atom beyond this radius;
  only density contributions above the (absolute) value specified with
  ``--rcut`` are taken into account,
* :ref:`Gaussian dampening (blurring) factor <blur>` --
  artificial temperature factor *B*\ :sub:`extra` added to all atomic
  B-factors (the structure factors are later corrected to cancel it out);
  either specified with ``--blur`` or picked automatically.

Choosing these parameters is a trade-off between efficiency and accuracy,
as described :ref:`elsewhere <blur>`.
The option ``--test`` can be used to see how accuracy and efficiency
depends on the choice of parameters.  For example, this shell script
performs a series of calculations with differing *B*\ :sub:`extra`:

.. code-block:: shell

  model=1mru.pdb
  dmin=2.5
  gemmi sfcalc --dmin=$dmin --test $model >cache.tsv
  for i in `seq -20 5 20`; do
      printf -- "$i\t" >&2
      gemmi sfcalc --dmin=$dmin --rate=1.5 --rcut=1e-4 --blur=$i --test=cache.tsv $model
  done >/dev/null

Running it prints:

.. code-block:: none

  -20	RMSE=0.93304  0.5495%  max|dF|=38.80  R=0.301%   0.27671s
  -15	RMSE=0.37007  0.2179%  max|dF|=41.26  R=0.094%   0.28366s
  -10	RMSE=0.27075  0.1595%  max|dF|=44.35  R=0.041%   0.29322s
  -5	RMSE=0.27228  0.1604%  max|dF|=47.59  R=0.029%   0.30459s
  0	RMSE=0.28903  0.1702%  max|dF|=50.95  R=0.029%   0.31399s
  5	RMSE=0.30806  0.1814%  max|dF|=54.35  R=0.032%   0.32527s
  10	RMSE=0.32847  0.1934%  max|dF|=57.92  R=0.036%   0.33360s
  15	RMSE=0.35028  0.2063%  max|dF|=61.66  R=0.041%   0.34181s
  20	RMSE=0.37283  0.2196%  max|dF|=65.44  R=0.047%   0.35380s

The error used in RMSE is the magnitude of the difference of two vectors:
\|F\ :sub:`approx` -- F\ :sub:`exact`\|.
The next column is RMSE normalized by the sum of \|F\ :sub:`calc`\|.
Then we have maximum error for a single reflection, and the wall time
of computations.
We can see that in this case negative "dampening" (subtracting about
10A\ :sup:`2` from all B-factors) improves both accuracy and performance.

.. _fprime:

fprime
======

Calculate anomalous scattering factors (*f\'* and *f\"*).
Uses `Cromer-Liberman <https://doi.org/10.1107/S0567739481000600>`_
algorithm with corrections from
`Kissel and Pratt <https://doi.org/10.1107/S0108767389010718>`_.
This and different approaches are discussed in the documentation
of the :ref:`underlying functions <anomalous>`.

.. literalinclude:: fprime-help.txt
   :language: console

Here is an example how to print *f'* and *f"* using gemmi, XrayDB,
CCP4 crossec and cctbx (pyFprime is not included because it is
a GUI-only program). The Chantler's data from XrayDB is probably
the most reliable one::

  $ gemmi fprime --wavelength=1.2 Se
  Element  E[eV]  Wavelength[A]      f'             f"
  Se      10332.0  1.2             -1.4186        0.72389

  $ python3 -c "import xraydb; print(xraydb.f1_chantler('Se', 10332.0), xraydb.f2_chantler('Se', 10332.0))"
  -1.4202028957329489 0.7100533627953146

  $ echo -e "atom SE\n cwav 1 1.2 0\n END" | crossec | grep ^SE
  SE          1.2000    -1.5173     0.7240

  $ cctbx.eltbx.show_fp_fdp --wavelength=1.2 --elements=Se
  Wavelength: 1.2 Angstrom

  Element: Se
    Henke et al.  : f'=-1.44568 , f''=0.757958
    Sasaki et al. : f'=-1.5104  , f''=0.724000
    diff f''=-2.29 %


.. _gemmi-reindex:

reindex
=======

Experimental.
See description of the :ref:`reindexing function <reindexing>` for more details.

Reindex reflections in MTZ file.

.. literalinclude:: reindex-help.txt
   :language: console


residues
========

List residues from a coordinate file, one per line.

.. literalinclude:: residues-help.txt
   :language: console

Example::

  $ gemmi residues -m '/3/*/(CYS,CSD)' 4pth.pdb
  Model 3
  A   85  CYS: N CA C O CB SG H HA HB2 HB3 HG
  A  152  CSD: N CA CB SG C O OD1 OD2 HA HB2 HB3

.. _gemmi-align:

align
=====

Sequence alignment (global, pairwise, affine gap penalty).
Used primarily for aligning the residues in the model's chains
to the full sequence from the SEQRES record.

.. literalinclude:: align-help.txt
   :language: console

For the testing purpose, it can align text strings.
For example, the Levenshtein distance can be calculated by setting
the gap opening penalty to zero::

    $ gemmi align -p --match=0 --gapo=0 --text-align Saturday Sunday
    Score: -3   CIGAR: 1M2I5M
    Saturday
    |  |.|||
    S--unday

This tool uses modified code from `ksw2 <https://github.com/lh3/ksw2>`_.
See the :ref:`Sequence alignment <sequence-alignment>` section for more details.

sg
==

Prints information about given space group.

.. literalinclude:: sg-help.txt
   :language: console

.. _gemmi-contents:

contents
========

Analyses and summarizes content of a coordinate file.
Inspired by CCP4 program ``rwcontents``.

By default, it prints atom count, estimated number of hydrogens in the protein,
molecular weight of the protein, ASU volume, Matthews coefficient
and the fractional volume of solvent in the crystal.

It has options to print other information -- see the help message below.

.. literalinclude:: contents-help.txt
   :language: console

.. _gemmi-contact:

contact
=======

Searches for contacts in a model.

.. literalinclude:: contact-help.txt
   :language: console

blobs
=====

Searches for unmodelled blobs in electron density.
Similar to "Validate > Unmodelled blobs..." in Coot.
For use in Dimple_.

.. _Dimple: https://ccp4.github.io/dimple/

.. literalinclude:: blobs-help.txt
   :language: console

h
==

Adds or removes hydrogens.

Hydrogen positions are determined from restraints from a monomer library.
If the restraints allow various directions to a hydrogen atom,
that atom is assigned one of possible positions and its occupancy is zeroed.

.. literalinclude:: h-help.txt
   :language: console

mondiff
=======

Compares restraints from two monomer CIF files.
It is intended for comparing restraints for the same monomer,
but generated with different programs (or different versions of the same
program).

The files should have format used by the CCP4/Refmac monomer library.
This format is supported by all major macromolecular refinement programs.

.. literalinclude:: mondiff-help.txt
   :language: console

wcn
===

Calculates Weighted Contact Number (WCN) and a few other similar metrics.

WCN can be used to predicts B-factors (ADPs) from coordinates,
and to compare this prediction with the values from refinement.

Background
----------

Protein flexibility and dynamic properties can be to some degree inferred
from the atomic coordinates of the structure. Various approaches are used
in the literature:
molecular dynamics, Gaussian or elastic network models, normal mode analysis,
calculation of solvent accessibility or local packing density, and so on.

Here we apply the simplest approach, which is pretty effective.
It originates from the
`2002 PNAS paper <http://www.pnas.org/content/99/3/1274>`_
in which Bertil Halle concluded that B-factors are more accurately predicted
by counting nearby atoms than by Gaussian network models. This claim was
based on the analysis of only 38 high resolution structures (and a neat theory),
but later on the method was validated on many other structures.

In particular, in 2007 Manfred Weiss brought this method to the attention
of crystallographers
by `analysing in Acta Cryst D <https://doi.org/10.1107/S0907444907052146>`_
different variants of the methods
on a wider set of more representative crystals.
Recently, the parameters fine-tuned by Weiss have been used for guessing
which high B-factors (high comparing with the predicted value) result
`from the radiation damage <https://doi.org/10.1107/S1600577515002131>`_.

Only a few months later, in 2008,
`Chih-Peng Lin et al. devised <https://doi.org/10.1002/prot.21983>`_
a simple yet significant improvement to the original Halle's method:
weighting the counted atoms by 1/*d*:sup:`2`, the inverse of squared distance.
It nicely counters the increasing average number of atoms with the distance
(~ *d*:sup:`2`).
This method was named WCN -- weighted contact number (hmm.. "contact").

These two methods are so simple that it seems easy to find a better one.
But according to my quick literature search, no better method of this kind
has been found yet. In 2009
`Li and Bruschweiler <https://doi.org/10.1016/j.bpj.2009.01.011>`_
proposed weighting that decreases exponentially (that model was named LCBM),
but in my hands it does not give better results than WCN.

`In 2016 Shahmoradi and Wilke <https://doi.org/10.1002/prot.25034>`_
did a data analysis aiming to disentangle the effects of local
and longer-range packing in the above methods.
They were not concerned with B-factors, though, but with
the rate of protein sequence evolution.
Because the "contact" methods predict many things.
Interestingly, if the exponent in WCN is treated as a parameter
(equal -2 in the canonical version), the value -2.3 gives the best results
in predicting evolution.

TLS
---

We also need to note that
`TLS <https://doi.org/10.1107/S0567740868001718>`_-like methods
that model B-factors as rigid-body motion of molecules are reported
to give better correlation with experimental B-factors
than other methods. But because such models use experimental B-factors on
the input and employ more parameters, they are not directly comparable
with WCN.

Unlike the TLS that is routinely used in the refinement of diffraction data,
the TLS modelling described here is isotropic.
It uses 10 parameters (anisotropic TLS requires 20) as described in a
`paper by Kuriyan and Weis <https://doi.org/10.1073/pnas.88.7.2773>`_ (1991).
`Soheilifard et al (2008) <https://doi.org/10.1088/1478-3975/5/2/026008>`_
got even better results by increasing B-factors at the protein ends,
using 13 parameters altogether. This model was named eTLS (e = extended).

The high effectiveness of the TLS model does not mean that B-factors
are dominated by the rigid-body motion. As noted by Kuriyan and Weis,
the TLS model captures also the fact that atoms in the interior of
a protein molecule generally have smaller displacements than those
on the exterior. Additionally, authors of the LCBM paper find that
the TLS model fitted to only half of the protein poorly fits
the other half, which suggests overfitting.

We may revisit rigid-body modelling in the future, but now we get back
to the contact numbers.

Details
-------

The overview above skipped a few details.

* While the WCN method is consistently called WCN,
  the Halle's method was named LDM (local density model) in the original paper,
  and is called CN (contact number) in some other papers. CN is memorable
  when comparing with WCN (which adds 'W' -- weighting)
  and with ACN (which adds 'A' -- atomic).

* These method are used either per-atom (for predicting B-factors, etc.)
  or per-residue (for evolutionary rate, etc.).
  So having "A" in ACN clarifies how it is used.
  To calculate the contact number per-residue one needs to pick
  a reference point in the residue (Cβ, the center of mass or something else),
  but here we do only per-atom calculations.

* The CN method requires a cut-off, and the cut-off values vary widely,
  from about 5 to 18Å. In the original paper it was 7.35Å,
  Weiss got 7.0Å as the optimal value, Shahmoradi 14.3Å.

* The CN can be seen as weighted by Heaviside step function,
  and smoothing it helps a little bit (as reported by both Halle and Weiss).

* Similarly to eTLS, the LCBM method has eLCBM variant that adds
  "end effects" -- special treatment of the termini.

* Finally, these methods may or may not consider the symmetry mates
  in the crystal. Halle checked that including symmetric images
  improves the prediction.
  Weiss (ACN) and Li and Bruschweiler (LCBM) are also taking symmetry into
  account. But I think other papers don't.

Metrics for comparison
----------------------

To compare a number of nearby atoms with B-factor we either rescale
the former, or we use a metric that does not require rescaling.
The Pearson correlation coefficient (CC) is invariant under linear
transformation,
so it can be calculated directly unless we would like to apply non-linear
scaling. Which was tried only in the Manfred Weiss' paper: scaling
function with three parameters improved CC by 0.012 comparing with linear
function (that has two parameters). Here, to keep it simple, we only do
linear scaling.

As noted by Halle, Pearson's CC as well as the mean-square deviation
can be dominated by a few outliers. Therefore Halle used relative mean
absolute deviation (RMAD): sum of absolute differences divided
by the average absolute deviation in the experimental values.
Halle justifies this normalization writing that it allows to compare
structures determined at different temperatures.
This is debatable as can be seen from ccp4bb
`discussions <https://www.mail-archive.com/ccp4bb@jiscmail.ac.uk/msg30444.html>`_
on how to compare B-factors between two structures.
But for sure RMAD is a more robust metric, so we also use it.
It adds another complication, though. To minimize the absolute deviation
we cannot use least-squares fitting, but rather quantile regression with q=0.5.

Another metric is the rank correlation. It is interesting because it is
invariant under any monotonic scaling. But it is not guaranteed to be
a good measure of similarity.

Results
-------

To be wrapped up and published. But in the meantime here are some thoughts:

* The optimal exponent is slightly larger than 2; the difference is small,
  so we prefer to use 2 (i.e. *w*\ =1/*r*:sup:`2`).

* Accounting for all symmetry mates (i.e. for intermolecular contacts
  in the crystal) improves the results -- and then the cut-off is necessary.

* The optimal cut-off is around 15A -- let's use 15A.

* Averaging predicted B-factors of nearby atoms helps; we use Gaussian
  smoothing (blurring) with σ around 2A.

* Pearson's CC around 0.8 may seem high, but it corresponds to R2=0.64,
  i.e. it we explain only 64% of the B-factor variance.
  Even less of the absolute deviation -- below 50%.

* Minimizing absolute deviation (with quantile regression)
  gives similar results as the ordinary least squares (OLS).
  The difference in terms of RMAS is only ~0.03.

* Combining WCN with CN is helping only a tiny bit (i.e. both are highly
  correlated) at the cost of additional parameter that is fitted.
  Combining WCN with rotation-only model (squared distance from the center
  of mass) increases CC slightly more, but still not much.

* Accounting for symmetry mates worsens prediction of evolutionary rates.
  I used `data <https://github.com/shahmoradi/cordiv>`_
  from Shahmoradi and Wilke to check this.


Program
-------

gemmi-wcn implements combination of the CN and WCN methods above.

Being based on a general-purpose crystallographic library it handles
corner cases that are often ignored. A good example is searching
for contacts. For most of the structures, considering only the same
and neighbouring unit cells (1+26) is enough.
But some structures have contacts between molecules several unit cells apart,
even with only :ref:`a single chain in the asu <long_chain>`.

TBC

.. literalinclude:: wcn-help.txt
   :language: console
