An Introduction to Best Practices in Free Energy Calculations

  • Michael R. ShirtsEmail author
  • David L. Mobley
Part of the Methods in Molecular Biology book series (MIMB, volume 924)


Free energy calculations are extremely useful for investigating small-molecule biophysical properties such as protein-ligand binding affinities and partition coefficients. However, these calculations are also notoriously difficult to implement correctly. In this chapter, we review standard methods for computing free energy via simulation, discussing current best practices and examining potential pitfalls for computational researchers performing them for the first time. We include a variety of examples and tips for how to set up and conduct these calculations, including applications to relative binding affinities and small-molecule solvation free energies.

Key words

Free energy calculation Alchemical methods Thermodynamic integration Bennett acceptance ratio WHAM MBAR Solvation free energy Binding free energy 



The authors wish to thank John Chodera (UC-Berkeley) for ongoing discussions of reliability and usability for free energy calculations as well as TriPham (UVa) and Justin Lemkul (Virginia Tech), Joe Allen (SUNY Stonybrook) for careful review of the manuscript.


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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Department of Chemical EngineeringUniversity of VirginiaCharlottesvilleUSA
  2. 2.Department of Pharmaceutical SciencesUniversity of CaliforniaIrvineUSA

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