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Chapter 7. Blabber: Generate Protomers

Blabber is a command-line tool for the protonation and deprotonation of molecular structures based on the MoKa pKa prediction engine.

Blabber input is a SD, mol2 (or multi-mol2) file; the file is analyzed with the MoKa engine to predict the pKa values. Ionizable sites are then protonated or deprotonated according to the chosen reference pH (by default, 7.4) and the final structure is saved in the SD format.

7.1. Blabber workflow

The following is a (simplified) scheme of the steps performed by Blabber on each input structure

load structure
store the structure "features" likely to be affected during computation: for SD files this includes formal charges, attached hydrogens, stereochemistry information, etc.
fill heavy atoms valences with hydrogens
convert to Kekule form
predict ionizable sites
calculate protonation state of ionizable sites at the given pH
for each ionizable site: hydrogens are removed and appropriate formal charges are applied
Restore "features" not affected by computation
output SD file

Warning

Though Blabber accepts input structures complete with hydrogens, the output will need to be post-processed by other tools. In particular, add hydrogens and 3D geometry optimization will be needed in order to use the resulting structure for other purposes (e.g. docking, virtual screening)

7.2. Command-line options

The full set of available options is shown when you run Blabber without parameters:

$ blabber_sd/blabber_sd 
Too few parameters on the command-line
usage: blabber_sd/blabber_sd [options] <filename>

 <filename> can be a SD (.sd or .sdf) or MOL2 (.mol2) file

options are:
 -h, --help                     display this help
     --version                  show version info
     --input-type=<sd|mol2>     input file type ( autodetect )
 -p <pH list>, --pH=<pH list>   report most abundant species
                                at given pH (7.4)
     --load-model=<database>    use a custom model database for predictions
 -o, --output=FILE              output file name (SD only)
 -t <abundance>                 report all species above the threshold

<ph list> is a comma separated list of the following:
    * single value
    * range ( min-max )
Examples:
    * single value:    --pH=6
    * single range:    --pH=6-10
    * multiple values: --pH=6,7,8
    * mixed:           --pH=6,7-10

7.2.1. Basic usage examples

All the following examples report the most abundant species at the given pH

blabber_sd -o charged.sdf myfile.sdf

reads myfile.sdf and outputs an SD (charged.sdf) with the correct protonation/deprotonation at pH 7.4.

blabber_sd -o charged.sdf myfile.mol2

the same as above, but using a mol2 file as input

blabber_sd -p3 -o charged.sdf myfile.sdf

the same as above, but predicting species at pH 3

7.2.2. Advanced usage examples

For each structure input there is sometimes the need to output more than one species. Blabber can handle this situation using the -t parameter as follows:

blabber_sd -t 25 -o charged.sdf myfile.sdf

with all of the species whose abundance is above the default threshold (25%) being reported in the output file.

For example, if myfile.sdf in the previous example is an amine with pKa=8.1, at pH 7.4, 81% of the amine is in the protonated form and 19% is in the neutral form so in charged.sdf Blabber would report only the protonated form, because the abundance of the neutral species is below the threshold.

Lowering the threshold value using:

blabber_sd -t 15 -o charged.sdf myfile.sdf

will let Blabber report both species in the output file.

When working with thresholds, a pH interval can also be defined. For example:

blabber_sd -t 15 -p5-9 -o charged.sdf myfile.sdf

outputs all species at any pH in the given range (5-9) more abundant than 15%.

7.3. Output format

The output from a typical Blabber run is reported below. In this example Blabber determined the most abundant species for pyridine at pH=4.5 to be the protonated one, with a predicted abundance of 75%

$ blabber_sd -p4.5 pyridine.sdf
Pyridine
-- Protonation normalized by MoKa v1.1.0-RC1-SNAPSHOT --

  6  6  0     0  0            999 V2000
    0.0000    1.5000    0.0000 C   0  0  0  0  0  0
    0.8500    2.0000    0.0000 C   0  0  0  0  0  0
    1.7250    1.5000    0.0000 C   0  0  0  0  0  0
    1.7250    0.5000    0.0000 C   0  0  0  0  0  0
    0.8500    0.0000    0.0000 N   0  3  0  0  0  0
    0.0000    0.5000    0.0000 C   0  0  0  0  0  0
  4  5  2  0
  5  6  1  0
  2  3  2  0
  1  2  1  0
  3  4  1  0
  1  6  2  0
M  CHG  1   5   1
M  END
>  <ABUNDANCE> 
74.99% at pH 4.5

$$$$

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Kibitzer: Extend pKa accuracy		Tauthor: Generate Tautomers