The binding free energy between a ligand and its target protein is an essential quantity to know at all stages of the drug discovery pipeline. Assessing this value computationally can offer insight into where efforts should be focused in the pursuit of effective therapeutics to treat myriad diseases. In this work we examine the computation of alchemical relative binding free energies with an eye to assessing reproducibility across popular molecular dynamics packages and free energy estimators. The focus of this work is on 54 ligand transformations from a diverse set of protein targets: MCL1, PTP1B, TYK2, CDK2 and thrombin. These targets are studied with three popular molecular dynamics packages: OpenMM, NAMD2 and NAMD3. Trajectories collected with these packages are used to compare relative binding free energies calculated with thermodynamic integration and free energy perturbation methods. The resulting binding free energies show good agreement between molecular dynamics packages with an average mean unsigned error between packages of 0.5 $kcal/mol$ The correlation between packages is very good with the lowest Spearman's, Pearson's and Kendall's tau correlation coefficient between two packages being 0.91, 0.89 and 0.74 respectively. Agreement between thermodynamic integration and free energy perturbation is shown to be very good when using ensemble averaging.
Thermodynamic stability of water molecules in the bacteriorhodopsin proton channel: a molecular dynamics free energy perturbation study