# Supporting data for 'The maximal and current accuracy of rigorous protein-ligand binding free energy calculations'
Gregory Ross, 18th October 2022

This folder contains input and output data for the results described in the manuscript "The maximal and current accuracy of 
rigorous protein-ligand binding free energy calculations".

## Contents

### experimental_survey_data
Publicly available data for ligands and proteins that have had their binding free energy measured by at least two dissimilar 
assays. The focus of this survey is on the _reproducibility_ of the measured binding free energy, as opposed to the 
_repeatability_ of a particular assay. 

The directory contains csv files, each of which lists the measurements from a pair of different assays. Each column 
corresponds to the measurements from a different method and the rows correspond to different ligands. 

Each CSV is named to help identify the published manuscript where the data was taken from, namely the surname of the 
first author followed by the year of publication. Please see the Supporting Information for the full reference and more
information on the data. 

### fep_benchmark_data
The inputs for running the binding free energy calculations for a large collection of targets and congeneric series of 
ligands. The predictions from the 21-4 release of FEP+ are also included. The development of these inputs is described 
in the supporting information. Improvement to these inputs could be considered and we recommend basing any improvements 
on free energy calculations.   


#### Sub-directories

##### structure_inputs
PDB files of the proteins and SDF files of the ligands. The ligands are tagged with their experimental binding free 
energy (in kcal/mol). These are the structural inputs that were used for FEP+. 

##### edge_predictions
The collection of CSV files that contain the raw outputs from FEP+ (21-4) using the structures from 'structural_inputs'. 
The columns correspond to
* The names of the ligands involved in the perturbation
* The experimental relative binding free energy
* The raw prediction from FEP+ ("Bennett ddG") and it's estimated error ("Bennett std. error")
* The cycle closure corrected predicted relative binding free energies ("CCC ddG") and their estimated error 
("CCC std. error")

The topology of the perturbation graph is defined by the edges in each CSV file. The direction of the edges is Lig1 -> Lig2.

##### ligand_predictions
Many of the edges in "edge_predictions" are between conformers, protomers, and tautomers of the same molecule. These 
must to processed to produce a single relative binding free energy for each molecule. The data in these CSV files are a
step towards that, as they contain predicted binding free energies after the application of conformer, rotamer symmetry,
and pka/tautomer corrections. After correction, different conformers and tautomers/protomers of the same molecules have 
the same predicted binding free energy. Rather than relative binding free energies, the CSV files contained here have
predicted _absolute_ binding free energies that are known up to an unknown additive constant. The additive constant was
set such that the mean of the predicted absolute binding free energies equals the mean of experimental binding free 
energies.

In each CSV file, the columns refer to
* The name of the ligand
* The experimental binding free energy
* The predicted binding free energy after corrections as well as the estimated standard error.

From these absolute predictions, the pairwise RMSEs can be calculated. Alternate conformers have been removed from the 
set of the predictions, but alternate protomers and tautomers are still listed - these should be accounted for when 
calculating the pairwise RMSE.


#### Benchmark arrangement
The FEP+ benchmark data set is divided into 14 different groups based on their origin. These directories of these groups are 
listed below, in alphabetical order, along with the section title of the Supporting Information that describes their 
development. The OPLS drug discovery data set that is listed in the Supporting information set will not be made publicly 
available.

* `bayer_macrocycles/`: Bayer Macrocycles
* `charge_annhil/`: FEP+ charge change set
* `fragments/`: FEP+ fragment data set
* `gpcrs/`: GPCRs
* `jacs_set/`: FEP+ R-group set
* `janssen_bace/`: Janssen BACE1 data sets
* `macrocycles/`: FEP+ macrocycles
* `mcs_docking/`: MCS docking sets
* `merck/`: The public Merck data set
* `misc/`: Miscellaneous data sets
* `opls_stress/`: OPLS stress set
* `scaffold_hoping/`: FEP+ scaffold hopping
* `waterset/`: FEP+ buried water set
