Absolute Alchemical Free Energy Calculations for Ligand Binding: A Beginner’s Guide

Part of the Methods in Molecular Biology book series (MIMB, volume 1762)


Many thermodynamic quantities can be extracted from computer simulations that generate an ensemble of microstates according to the principles of statistical mechanics. Among these quantities is the free energy of binding of a small molecule to a macromolecule, such as a protein. Here, we present an introductory overview of a protocol that allows for the estimation of ligand binding free energies via molecular dynamics simulations. While we focus on the binding of organic molecules to proteins, the approach is in principle transferable to any pair of molecules.

Key words

Free energy Computer simulations Molecular dynamics Alchemical transitions Protein–ligand binding Binding free energy Binding affinity Drug design Molecular modeling 



The EPSRC and Evotec via the Systems Approaches to Biomedical Sciences Doctoral Training Centre (EP/G037280/1) support M.A. J.B. is supported by the EPSRC/MRC via the Systems Approaches to Biomedical Sciences Doctoral Training Centre (EP/G037280/1) with additional support from GSK. We thank David Mobley (University of California, Irvine), John Chodera (MSKCC), and Michael Shirts (University of Colorado, Boulder) for sharing their extensive experience on alchemical free energy calculations through publicly available platforms and personal communications. Work in PCB’s laboratory is currently supported by the MRC, BBSRC, and the John Fell Fund. We thank the Advanced Research Computing (ARC) facility, the EPSRC UK National Service for Computational Chemistry Software (NSCCS) at Imperial College London (grant no. EP/J003921/1), and the ARCHER UK National Supercomputing Services for computer time granted via the UK High-End Computing Consortium for Biomolecular Simulation, HECBioSim (, supported by EPSRC (grant no. EP/L000253/1).


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Authors and Affiliations

  1. 1.Structural Bioinformatics and Computational Biochemistry, Department of BiochemistryUniversity of OxfordOxfordUK
  2. 2.Department of Theoretical and Computational BiophysicsMax Planck Institute for Biophysical ChemistryGöttingenGermany

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