Calculation of Binding Free Energies

  • Vytautas Gapsys
  • Servaas Michielssens
  • Jan Henning Peters
  • Bert L. de GrootEmail author
  • Hadas Leonov
Part of the Methods in Molecular Biology book series (MIMB, volume 1215)


Molecular dynamics simulations enable access to free energy differences governing the driving force underlying all biological processes. In the current chapter we describe alchemical methods allowing the calculation of relative free energy differences. We concentrate on the binding free energies that can be obtained using non-equilibrium approaches based on the Crooks Fluctuation Theorem. Together with the theoretical background, the chapter covers practical aspects of hybrid topology generation, simulation setup, and free energy estimation. An important aspect of the validation of a simulation setup is illustrated by means of calculating free energy differences along a full thermodynamic cycle. We provide a number of examples, including protein–ligand and protein–protein binding as well as ligand solvation free energy calculations.

Key words

Free energy Molecular dynamics Alchemical transitions Protein–ligand binding Protein–protein interaction Non-equilibrium methods Hybrid topology Crooks Fluctuation Theorem 


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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Vytautas Gapsys
    • 1
  • Servaas Michielssens
    • 1
  • Jan Henning Peters
    • 1
  • Bert L. de Groot
    • 1
    Email author
  • Hadas Leonov
    • 1
  1. 1.Max Planck Institute for Biophysical ChemistryGöttingenGermany

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