ProteinLigandBenchmarks

Protein-Ligand Benchmark Dataset for testing Parameters and Methods of Free Energy Calculations.

Documentation

Documentation for the protein-ligand-benchmark package is hosted at readthedocs.

Related Publication

The preprint on "Best practices for constructing, preparing, and evaluating protein-ligand binding affinity benchmarks" provides accompanying information to this benchmark dataset and how to use it for alchemical free energy calculations. For any suggestions of improvements please raise an issue in its GitHub repository.

Installation

The repository uses git-lfs (large file storage) for the storage of all the data file. Ideally git-lfs is installed first before cloning the repository.

conda create -n plbenchmark python=3.7 git-lfs
conda activate plbenchmark
git lfs clone https://github.com/openforcefield/protein-ligand-benchmark.git
cd protein-ligand-benchmark
conda env update --file environment.yml
pip install -e .

Getting Started

Example notebooks can be found in the Documentation and in examples. Paper repository here.

Data file tree and file description

The data is organized as followed:

data
├── targets.yml                               # list of all targets and their directories   
├── <date>_<target_name_1>                    # directory for target 1
│   ├── 00_data                               #     metadata for target 1
│   │   ├── edges.yml                         #         edges/perturbations
│   │   ├── ligands.yml                       #         ligands and activities
│   │   └── target.yml                        #         target
│   ├── 01_protein                            #     protein data
│   │   ├── crd                               #         coordinates
│   │   │   ├── cofactors_crystalwater.pdb    #             cofactors and cyrstal waters (might be empty if there are none)  
│   │   │   └── protein.pdb                   #             aminoacid residues   
│   │   └── top                               #         topology(s)
│   │   │   └── amber99sb-star-ildn-mut.ff    #             force field spec.     
│   │   │       ├── cofactors_crystalwater.top#                 Gromacs TOP file of cofactors and crystal water (might be empty if there are none)
│   │   │       ├── protein.top               #                 Gromacs TOP file of amino acid residues
│   │   │       └── *.itp                     #                 Gromacs ITP file(s) to be included in TOP files
│   └── 02_ligands                            #     ligands
│   ├── lig_<name_1>                          #          ligand 1 
│   │   ├── crd                               #              coordinates
│   │   │   └── lig_<name_1>.sdf              #                  SDF file
│   │   └── top                               #              topology(s)
│   │       └── openff-1.0.0.offxml           #                  force field spec.       
│   │           ├── fflig_<name_1>.itp        #                      Gromacs ITP file : atom types     
│   │           ├── lig_<name_1>.itp          #                      Gromacs ITP file       
│   │           ├── lig_<name_1>.top          #                      Gromacs TOP file                
│   │           └── posre_lig_<name_1>.itp    #                      Gromacs ITP file : position restraint file  
│   ├── lig_<name_2>                          #         ligand 2                               
│   …                                        
│   └── 03_hybrid                             #    edges (perturbations)
│   ├── edge_<name_1>_<name_2>                #         edge between ligand 1 and ligand 2   
│   │   └── water                             #             edge in water 
│   │       ├── crd                           #                 coordinates 
│   │       │   ├── mergedA.pdb               #                     merged conf based on coords of ligand 1  
│   │       │   ├── mergedB.pdb               #                     merged conf based on coords of ligand 2   
│   │       │   ├── pairs.dat                 #                     atom mapping                  
│   │       │   └── score.dat                 #                     similarity score         
│   │       └── top                           #                 topology(s)       
│   │           └── openff-1.0.0.offxml       #                     force field spec.         
│   │               ├── ffmerged.itp          #                         Gromacs ITP file  
│   │               ├── ffMOL.itp             #                         Gromacs ITP file   
│   │               └── merged.itp            #                         Gromacs ITP file     
│   …                                        
├── <date>_<target_name_2>                    # directory for target 2  
…

Description of meta data YAML files

targets.yml

This file lists all the registered targets in the benchmark set. Each entry denotes one target and contains the following information:

mcl1_sample:
  name:     mcl1_sample
  date:     2020-08-26
  dir:      2020-08-26_mcl1_sample

mcl1_sample is the entry name and each entry has three sub-entries:

• name is the target name, which is usually the same as the entry name of the target.
• date is the date when the target was initially added to the benchmark set.
• dir is the directory name where all the data for the target is found. Usually it is the date and the name field, connected by a underscore _.

target.yml

This file is found in the meta data directory of each target: <date>_<target_name>/00_data/target.yml. It contains additionally information about the target:

alternate:
  iridium_classifier: HT
  iridium_score: 0.3
  pdb: 6O6F
associated_sets:
- Schrodinger JACS
comments: hydrophobic interactions contributing to binding
date: 2019-12-13
dpi: 0.26
id: 9
iridium_classifier: HT
iridium_score: 0.41
name: mcl1
netcharge: 4 e
pdb: 4HW3
references:
  calculation:
  - 10.1021/ja512751q
  - 10.1021/acs.jcim.9b00105
  - 10.1039/C9SC03754C
  measurement:
  - 10.1021/jm301448p

Explanation of the entries:

• alternate: Alternate X-ray structure which could be used
  • iridium_classifier: Iridium classifier of the alternate structure
  • iridium_score: Iridium score of the alternate structure
  • pdb: PDB ID of the alternate structure
• associated_sets: list of benchmark set tags, where this target is in (e.g. "Schrodinger JACS")
• comments: hydrophobic interactions contributing to binding
• date: date when the target was initially added to the benchmark set.
• dpi: diffraction precision index of the used structure (quality metric for the structure)
• id: a given ID
• iridium_classifier: Iridium classifier of the used structure
• iridium_score: Iridium score of the used structure
• name: name/identifier of the target
• netcharge: total charge of the prepared protein (this should be equalized with counter ions during preparation of the simulation system)
• pdb: PDB ID of the used structure
• references: doi to references
  • calculation: list of references where this target was used in calculations
  • measurement: list of references of affinity measurements

ligands.yml

This file is found in the meta data directory of each target: <date>_<target_name>/00_data/ligands.yml. It contains information of the ligands of one target. One entry looks like this:

lig_23:
  measurement:
    comment: Table 2, entry 23
    doi: 10.1021/jm301448p
    error: 0.03
    type: ki
    unit: uM
    value: 0.37
  name: lig_23
  smiles: '[H]c1c(c(c2c(c1[H])c(c(c(c2OC([H])([H])C([H])([H])C([H])([H])C3=C(Sc4c3c(c(c(c4[H])[H])[H])[H])C(=O)[O-])[H])[H])[H])[H])[H]'

Explanation of the entries:

• measurement: affinity measurement entry
  • comment: comment about the measurement
  • doi: DOI (digital object identifier) pointing to the reference for this measurement
  • error: Error of measurement, null if not reported
  • type: type of measurement observable, ki (binding equilibrium constant), ic50 (IC50 value), pic50 (pIC50 value), or dg (free energy of binding) are accepted entries.
  • unit: Unit of value and error entries.
  • value: Value of the measurement.
• name: name of ligand, which always starts with lig_, followed by a unique identifier.
• smiles: SMILES string of the ligand, with charge state information and chirality information.

edges.yml

This file is found in the meta data directory of each target: <date>_<target_name>/00_data/edges.yml. It contains information of the edges of one target. One entry looks like this:

edge_50_60:
  ligand_a: lig_50
  ligand_b: lig_60

Each entry is just a list of two ligand identifiers.

Summary

Summary of the contents of the Protein-Ligand Benchmark Dataset. It contains the available protein targets with corresponding PDB ID and number of ligands.

Target	PDB	N. Lig.
bace	4DJW	36
bace_hunt	4JPC	32
bace_p2	3IN4	12
cdk2	1H1Q	16
cdk8	5HNB	33
cmet	4R1Y	12
eg5	3L9H	28
galectin	5E89	8
hif2a	5TBM	42
jnk1	2GMX	21
mcl1	4HW3	42
p38	3FLY	34
pde10	4BBX	35
pde2	6EZF	21
pfkfb3	6HVI	40
ptp1b	2QBS	23
shp2	5EHR	26
syk	4PV0	44
thrombin	2ZFF	11
tnks2	4UI5	27
tyk2	4GIH	16

Release History

Releases follow the major.minor.micro scheme recommended by PEP440, where

• major increments denote a change that may break API compatibility with previous major releases
• minor increments denote addition of new targets or addition and larger changes to the API
• micro increments denote bugfixes, addition of API features, changes of coordinates or topologies, and changes of metadata

Contributions

• Authors David Hahn
• Data Contributors The authors of the following publications, especially Vytautas Gapsys and Christina E. M. Schindler.
  • V. Gapsys et al., Large scale relative protein ligand binding affinities using non-equilibrium alchemy, Chem. Sci., 2020,11, 1140-1152
  • Christina E. M. Schindler et al., Large-Scale Assessment of Binding Free Energy Calculations in Active Drug Discovery Projects, J. Chem. Inf. Model. 2020, 60, 11, 5457–5474
  • Laura Perez Benito et al., Predicting Activity Cliffs with Free-Energy Perturbation, J. Chem. Theory Comput. 2019, 15, 3, 1884–1895
• Discussions and Suggestions Christopher I. Bayly, Marko Breznik, Hannah E. Bruce Macdonald, John D.Chodera, Katharina Meier, Antonia S. J. S. Mey, David L. Mobley, Laura Perez Benito, Gary Tresadern, Gregory L. Warren and all members of the Open Force Field Initiative
• Code review and discussions Matt Thompson, Jeffrey Wagner

License

MIT. See the License File for more information.

CC-BY-4.0 for data (content of directory data). See the License File for more information.

Copyright

Copyright (c) 2021, Open Force Field Consortium, David F. Hahn

Acknowledgements

Project based on the Computational Molecular Science Python Cookiecutter version 1.1.