FEP vs MM/GBSA: The Free-Energy Ladder from End-Point to Alchemical

By BioDockify Computational Research Team · October 17, 2026 · Tutorials

Where MM/GBSA ends and free energy perturbation begins: the alchemical idea, relative vs absolute FEP, cycle closures, what each method costs in compute and accuracy, and how to choose the right rung for your question.

Read the complete article with tables, code and references on BioDockify.

Key References

• Jorgensen, W.L. & Thomas, L.L. Perspective on free-energy perturbation calculations for chemical relative binding energies of small ligands in proteins. Curr. Opin. Chem. Biol. 12, 306-310 (2008).
• Wang, L. et al. Accurate and reliable prediction of relative ligand binding potency in prospective drug discovery by way of a modern free-energy calculation and docking pipeline. J. Am. Chem. Soc. 137, 2695-2703 (2015).
• Hou, T., Wang, J., Li, Y. & Wang, W. Assessing the performance of the MM/PBSA and MM/GBSA methods. WIREs Comput. Mol. Sci. 1, e85 (2011). DOI: 10.1002/wcms.95
• Bhati, A.P., Wan, S., Hu, Y. et al. Binding free energy calculations for UK-1 series. Sci. Rep. 9, 4245 (2019).

Scope & Limitations

FEP accuracy requires adequate sampling of both end states; charged perturbations and large scaffold changes remain hard regardless of method Prospective FEP performance is target-class dependent; past benchmark success does not transfer automatically to novel pockets