PROPKA 3: Heuristic \(\text{p}K_\text{a}\) prediction¶

Release: 3.4.0+0.g68007f0.dirty
Date: Dec 19, 2020

PROPKA 3 predicts the \(\text{p}K_\text{a}\) values of ionizable groups in proteins [Sondergaard2011] and protein-ligand complexes based on the 3D structure [Olsson2011].

This package installs the propka3 command and the propka Python package.

License and source code¶

PROPKA 3 is released under the GNU Lesser General Public License v2.1 (see the files LICENSE in the repository for details).

Source code is available in the public GitHub repository https://github.com/jensengroup/propka.

Getting help¶

Please report bugs and feature requests for PROPKA through the Issue Tracker.

Contributing¶

PROPKA welcomes new contributions. To contribute code, submit a pull request against the master branch in the propka repository.

Citation¶

If you use PROPKA 3 in published work please cite [Sondergaard2011] and [Olsson2011].

Indices and tables¶

Installation¶

PROPKA 3 requires Python 3.6 or higher. Additional requirements are specified in the requirements.txt file and automatically satisfied when installing with pip.

`pip`-based installation¶

The easiest way to install a release of PROPKA 3 is from the PyPI archive with the command

pip install --upgrade propka

This installation will install the propka Python module and the propka3 executable script. As always, a virtual environment (e.g., via virtualenv) is recommended when installing packages.

Source-based installation¶

The source code can be installed by cloning the repository or unpacking from a source code archive and running

pip install .

in the source directory.

For the purposes of testing or development, you may prefer to install PROPKA as an editable module via pip by running

pip install -e .

in the source directory.

Quickstart Guide¶

PROPKA can be used either via the installed script propka3 or as a Python module. When using the propka3 command, use

propka3  FILENAME

As a module (propka), also provide the input filename

python -m propka FILENAME

In both cases, additional options may be added, as described in more detail for the propka3 command.

Predicting protein residue \(\text{p}K_\text{a}\) values¶

Most users run PROPKA by invoking the propka3 program with a PDB file as its argument; e.g., for PDB 1HPX (HIV-1 protease complexed with the inhibitor KNI-272)

propka3 1hpx.pdb

In this example, \(\text{p}K_\text{a}\) values of titratable protein residues and titratable groups of the inhibitor KNI are calculated.

The output looks similar to the following (many lines omitted as “…”). It is also contained in the output file 1hpx.pka that is automatically written:

propka3.2                                                                                    2020-06-19
...
...
Found NAR group:  1530-  N1   900-KNI (B) [   7.907    1.459    5.427] N
Found O3  group:  1531-  O1   900-KNI (B) [   5.235    3.791    9.082] O
Found O2  group:  1532-  O3   900-KNI (B) [   3.327    4.297   11.852] O
Found NAM group:  1533-  N2   900-KNI (B) [   3.955    2.384   10.893] N
Found O2  group:  1539-  O6   900-KNI (B) [   3.758   -0.629   12.111] O
Found NAM group:  1541-  N3   900-KNI (B) [   4.496    0.982   13.492] N
Found O2  group:  1542-  O4   900-KNI (B) [   6.324   -1.234   17.045] O
Found OH  group:  1548-  O2   900-KNI (B) [   4.949    0.934   16.427] O
Found O2  group:  1559-  O5   900-KNI (B) [   6.746   -3.574   14.588] O
Found NAM group:  1560-  N5   900-KNI (B) [   7.637   -4.575   16.403] N
-------------------------------------------------------------------------------------------------------


Calculating pKas for Conformation container 1A with 1878 atoms and 480 groups
-------------------------------------------------------------------------------------------------------

---------  -----   ------   ---------------------    --------------    --------------    --------------
                            DESOLVATION  EFFECTS       SIDECHAIN          BACKBONE        COULOMBIC
 RESIDUE    pKa    BURIED     REGULAR      RE        HYDROGEN BOND     HYDROGEN BOND      INTERACTION
---------  -----   ------   ---------   ---------    --------------    --------------    --------------

ASP  25 A   5.07*  100 %    4.30  617   0.19    0   -0.85 KNI  O4 B   -0.63 GLY  27 A    0.07 ASP  29 A
ASP  25 A                                           -0.85 KNI  O2 B   -0.09 ALA  28 A    0.00 XXX   0 X
ASP  25 A                                           -0.84 ASP  25 B   -0.04 GLY  27 B    0.00 XXX   0 X

ASP  29 A   3.11    50 %    1.20  420   0.13    0   -0.68 ARG  87 A    0.00 XXX   0 X   -0.04 LYS  45 A
ASP  29 A                                           -0.28 ARG   8 B    0.00 XXX   0 X   -0.47 ARG  87 A
ASP  29 A                                            0.00 XXX   0 X    0.00 XXX   0 X   -0.54 ARG   8 B

ASP  30 A   4.62    59 %    1.30  446   0.00    0   -0.11 LYS  45 A    0.00 XXX   0 X   -0.07 ARG  87 A
ASP  30 A                                            0.00 XXX   0 X    0.00 XXX   0 X   -0.01 ARG   8 B
ASP  30 A                                            0.00 XXX   0 X    0.00 XXX   0 X    0.29 ASP  29 A
ASP  30 A                                            0.00 XXX   0 X    0.00 XXX   0 X   -0.57 LYS  45 A

ASP  60 A   2.55     0 %    0.41  249   0.00    0   -0.40 THR  74 A    0.00 XXX   0 X   -0.02 LYS  45 A
ASP  60 A                                           -0.85 LYS  43 A    0.00 XXX   0 X   -0.38 LYS  43 A
...
...
...
ARG  87 B  12.28    45 %   -1.40  407   0.00    0    0.77 ASP  29 B    0.00 XXX   0 X    0.10 ASP  30 B
ARG  87 B                                            0.00 XXX   0 X    0.00 XXX   0 X   -0.19 ARG   8 A
ARG  87 B                                            0.00 XXX   0 X    0.00 XXX   0 X    0.50 ASP  29 B

N+    1 B   8.96     0 %   -0.39  235   0.00    0    0.85 C-   99 A    0.00 XXX   0 X    0.07 CYS  67 B
N+    1 B                                            0.00 XXX   0 X    0.00 XXX   0 X    0.04 CYS  95 B
N+    1 B                                            0.00 XXX   0 X    0.00 XXX   0 X    0.38 C-   99 A

KNI  N1 B   4.60     0 %   -0.36  273   0.00    0    0.00 XXX   0 X    0.00 XXX   0 X   -0.03 ARG   8 A

Coupled residues (marked *) were detected.Please rerun PropKa with the --display-coupled-residues
or -d option for detailed information.

--------------------------------------------------------------------------------------------------------
SUMMARY OF THIS PREDICTION
       Group      pKa  model-pKa   ligand atom-type
   ASP  25 A     5.07       3.80
   ASP  29 A     3.11       3.80
   ASP  30 A     4.62       3.80
   ASP  60 A     2.55       3.80
   ASP  25 B     9.28       3.80
   ASP  29 B     1.78       3.80
   ASP  30 B     4.91       3.80
   ASP  60 B     2.13       3.80
   GLU  21 A     4.78       4.50
   GLU  34 A     3.93       4.50
   GLU  35 A     3.65       4.50
   GLU  65 A     3.89       4.50
   GLU  21 B     4.73       4.50
   GLU  34 B     3.36       4.50
   GLU  35 B     4.07       4.50
   GLU  65 B     3.70       4.50
   C-   99 A     2.08       3.20
   C-   99 B     2.11       3.20
   HIS  69 A     6.98       6.50
   HIS  69 B     7.11       6.50
   CYS  67 A     9.41       9.00
   CYS  95 A    11.68       9.00
   CYS  67 B     9.82       9.00
   CYS  95 B    11.61       9.00
   TYR  59 A     9.67      10.00
   TYR  59 B     9.54      10.00
   LYS  14 A    10.43      10.50
   LYS  20 A    10.32      10.50
   LYS  43 A    11.41      10.50
   LYS  45 A    10.54      10.50
   LYS  55 A    10.42      10.50
   LYS  70 A    10.92      10.50
   LYS  14 B    10.55      10.50
   LYS  20 B    11.01      10.50
   LYS  43 B    11.43      10.50
   LYS  45 B    10.47      10.50
   LYS  55 B    10.41      10.50
   LYS  70 B    11.07      10.50
   ARG   8 A    13.96      12.50
   ARG  41 A    12.41      12.50
   ARG  57 A    14.40      12.50
   ARG  87 A    12.35      12.50
   ARG   8 B    12.76      12.50
   ARG  41 B    12.42      12.50
   ARG  57 B    13.73      12.50
   ARG  87 B    12.28      12.50
   N+    1 A     8.96       8.00
   N+    1 B     8.96       8.00
   KNI  N1 B     4.60       5.00                NAR

Writing 1hpx.pka

Some of the important contents:

The section Calculating pKas for Conformation container 1A with 1878 atoms and 480 groups lists details on the calculations for all ionizable residues. It indicates the considerations that went into a \(\text{p}K_\text{a}\) estimate such as hydrogen bonds and Coulomb interactions. It also indicates if there is potentially coupling between residues.
Values with “XXX” placeholders are not calculated (but appear to maintain the formatting).
The section SUMMARY OF THIS PREDICTION lists the predicted \(\text{p}K_\text{a}\) for each residue together with the model \(\text{p}K_\text{a}\) (the “default” value).
Ligand values are labeled with the residue name of the ligand, in this case “KNI”.

Getting help¶

A brief list of available options can be obtained by running PROPKA with no options. A longer list of options and descriptions is available using the propka3 --help option:

propka3 --help

propka3 command¶

PROPKA predicts the pKa values of ionizable groups in proteins and protein-ligand complexes based in the 3D structure. The propka3 command has the following options:

propka3 [-h] [-f FILENAMES] [-r REFERENCE] [-c CHAINS] [-i TITRATE_ONLY] [-t THERMOPHILES] [-a ALIGNMENT] [-m MUTATIONS]
       [-v VERSION_LABEL] [-p PARAMETERS] [--log-level {DEBUG,INFO,WARNING,ERROR,CRITICAL}] [-o PH] [-w WINDOW WINDOW WINDOW]
       [-g GRID GRID GRID] [--mutator MUTATOR] [--mutator-option MUTATOR_OPTIONS] [-d] [-l] [-k] [-q] [--protonate-all]
       input_pdb

input_pdb¶: read data from file <input_pdb>

-h, --help¶: show this help message and exit

-f FILENAMES, --file FILENAMES¶: read data from <filename>, i.e. <filename> is added to arguments (default: [])

-r REFERENCE, --reference REFERENCE¶: setting which reference to use for stability calculations [neutral/low-pH] (default: neutral)

-c CHAINS, --chain CHAINS¶: creating the protein with only a specified chain. Specify ” ” for chains without ID [all] (default: None)

-i TITRATE_ONLY, --titrate_only TITRATE_ONLY¶: Treat only the specified residues as titratable. Value should be a comma-separated list of “chain:resnum” values; for example: -i "A:10,A:11" (default: None)

-t THERMOPHILES, --thermophile THERMOPHILES¶: defining a thermophile filename; usually used in ‘alignment-mutations’ (default: None)

-a ALIGNMENT, --alignment ALIGNMENT¶: alignment file connecting <filename> and <thermophile> [<thermophile>.pir] (default: None)

-m MUTATIONS, --mutation MUTATIONS¶: specifying mutation labels which is used to modify <filename> according to, e.g. N25R/N181D (default: None)

--version¶: show program’s version number and exit

-p PARAMETERS, --parameters PARAMETERS¶: set the parameter file (default: <installation_directory>/propka/propka/propka.cfg)

--log-level {DEBUG,INFO,WARNING,ERROR,CRITICAL}¶: logging level verbosity (default: INFO)

-o PH, --pH PH¶: setting pH-value used in e.g. stability calculations (default: 7.0)

-w WINDOW WINDOW WINDOW, --window WINDOW WINDOW WINDOW¶: setting the pH-window to show e.g. stability profiles (default: (0.0, 14.0, 1.0))

-g GRID GRID GRID, --grid GRID GRID GRID¶: setting the pH-grid to calculate e.g. stability related properties (default: (0.0, 14.0, 0.1))

--mutator MUTATOR¶: setting approach for mutating <filename> [alignment/scwrl/jackal] (default: None)

--mutator-option MUTATOR_OPTIONS¶: setting property for mutator [e.g. type=”side-chain”] (default: None)

-d, --display-coupled-residues¶: Displays alternative pKa values due to coupling of titratable groups (default: False)

-l, --reuse-ligand-mol2-files¶: Reuses the ligand mol2 files allowing the user to alter ligand bond orders (default: False)

-k, --keep-protons¶: Keep protons in input file (default: False)

-q, --quiet¶: suppress non-warning messages (default: None)

--protonate-all¶: Protonate all atoms (will not influence pKa calculation) (default: False)

API Reference¶

The propka3 command provides a command-line interface to PROPKA 3’s functionality. It is built on classes and functions in the propka module. The API of propka is documented here for developers who might want to directly use the PROPKA 3 code.

Note

The API is still changing and there is currently no guarantee that it will remain stable between minor releases.

Data structures¶

`atom`	Atom
`bonds`	Bonds
`group`	Data structures for groups
`conformation_container`	Molecular data structures
`molecular_container`	PDB molecular container

I/O¶

`input`	Input handling
`lib`	Set-up of a PROPKA calculation
`output`	Output
`parameters`	Configuration file parameters
`hybrid36`	Hybrid36 PDB-like file format
`ligand_pka_values`	Ligand pKa values from Marvin
`run`	Script functionality
`version`	Version-based configuration

Structure processing¶

`protonate`	Protonate a structure
`hydrogens`	Hydrogens
`ligand`	Ligand atom typing

Calculations¶

`calculations`	Calculations
`coupled_groups`	Coupling between groups
`determinant`	Determinant
`determinants`	Working with Determinants
`energy`	Energy calculations
`iterative`	Working with Determinants
`vector_algebra`	Vector calculations

Changelog¶

v3.4.0¶

Changes¶

Removed PROPKA input support and argument --generate-propka-input (#99)
Add Python 3.9 support to continuous integration. (#101)
Removed logging abstraction from code to facilitate debugging and reduce code bloat. (#108)

Fixes¶

Fixed bug that raised exception when missing amide nitrogen or oxygen. (#17)
propka --version now shows the program version and exits. Previously this option took a version argument to specify the sub-version of propka. However, this was non-functional at least since 2012. (#89)
Fix pI reporting in last line of .pka file. (https://github.com/jensengroup/propka/pull/91)
Report correct version in .pka file header. (https://github.com/jensengroup/propka/pull/92)
Fix handling of multi-model PDB without MODEL 1 entry. (https://github.com/jensengroup/propka/issues/96)
Fixed bug and sped up algorithm for identifying bonds via bounding boxes. (#97, #110)
Fixed bug in propka --display-coupled-residues that crashed the program. (#105)

v3.3.0¶

Additions¶

Add Sphinx documentation on readthedocs.io (#69, #76, #79)

Changes¶

Updated read_molecule_file() to accept file-like objects. (#83)
Use versioneer for version management. (#87)
Add code coverage to continuous integration pipeline. (#62, #71, #76)

Fixes¶

Bundle required JSON files with package. (#48)
Fixed KeyError bug in read_parameter_file(). (#65)
Update links to web server. (#80)
Fixed PDB reading for PROPKA “single” runs. (#82)

v3.2.0¶

Additions¶

Significantly expanded testing framework. (#30, #36, #37)

Changes¶

Improved ability to use PROPKA as a module in other Python scripts. (#8)
Improved output via logging. (#11, #12)
Replaced data/parameter pickle file with human-readable JSON. (#29)
Significant delinting and formatting standardization against PEP8. (#33, #40)
Improved package documentation. (#41, #61)
Significant package refactoring. (#46, #47, #59)
Simplify module import structure. (#49, #61)
Improved tempfile handling. (#61)

v3.1.0¶

Archaeologists wanted to help us document the history of the code in versions 3.1.0 and earlier.

References¶

Sondergaard2011: C. R. Søndergaard, M. H. M. Olsson, M. Rostkowski, and J. H. Jensen. Improved treatment of ligands and coupling effects in empirical calculation and rationalization of pKa values. Journal of Chemical Theory and Computation, 7(7):2284–2295, 2011. doi: 10.1021/ct200133y
Olsson2011: M. H. M. Olsson, C. R. Søndergaard, M. Rostkowski, and J. H. Jensen. PROPKA3: Consistent treat- ment of internal and surface residues in empirical pKa predictions. Journal of Chemical Theory and Computation, 7(2):525–537, 2011. doi: 10.1021/ct100578z

PROPKA 3: Heuristic \(\text{p}K_\text{a}\) prediction¶

License and source code¶

Getting help¶

Contributing¶

Citation¶

Indices and tables¶

Installation¶

pip-based installation¶

Source-based installation¶

Quickstart Guide¶

Predicting protein residue \(\text{p}K_\text{a}\) values¶

Getting help¶

propka3 command¶

API Reference¶

Data structures¶

I/O¶

Structure processing¶

Calculations¶

Changelog¶

v3.4.0¶

Changes¶

Fixes¶

v3.3.0¶

Additions¶

Changes¶

Fixes¶

v3.2.0¶

Additions¶

Changes¶

v3.1.0¶

References¶

`pip`-based installation¶