Standard binding free energies from computer simulations: What is the best strategy? Accurate prediction of standard binding free energies describing protein–ligand association remains a daunting computational endeavor. This challenge is rooted to a large extent in the considerable changes in conformational, translational, and rotational entropies underlying the binding process that atomistic simulations cannot easily sample. In spite of significant methodological advances, reflected in a continuously improving agreement with experiment, a characterization of alternate strategies aimed at measuring binding affinities, notably their respective advantages and drawbacks, is somewhat lacking. Here, two distinct avenues to determine the standard binding free energy are compared in the case of a short, proline-rich peptide associating to the Src homology domain 3 of tyrosine kinase Abl. These avenues, one relying upon alchemical transformations and the other on potentials of mean force (PMFs), invoke a series of geometrical restraints acting on collective variables designed to alleviate sampling limitations inherent to classical molecular dynamics simulations. The experimental binding free energy of ΔGbind = −7.99 kcal/mol is well reproduced by the two strategies developed herein, with ΔGbind = −7.7 for the alchemical route and ΔGbind = −7.8 kcal/mol for the alternate PMF-based route. In detailing the underpinnings of these numerical strategies devised for the accurate determination of standard binding free energies, many practical elements of the proposed rigorous, conceptual framework are clarified, thereby paving way to tackle virtually any recognition and association phenomenon. J. Chem. Theory Comput. 2013.

Recent publications

Comer, J.; Schulten, K.; Chipot, C.
Calculation of lipid-bilayer permeabilities using an average force
J.Chem. Theory Comput.
  2014, 10 (2), 554-564.

Marquardt, R.; Hénin, J.; Dehez, F.; Chipot, C.,
Dynamiques moléculaires quantiques et classiques
L’Actualité Chimique
  2014,  (382-383), 56-62.

Comer, J.; Roux, B.; Chipot, C.;
Achieving ergodic sampling using replica-exchange free-energy calculations
Mol. Sim.
  2014, 40 (1-3),  218-228.


- A position for a postdoctoral candidate is opened. Contact us for more information.
- An update of ParseFEP is available in the latest version of VMD.
- 新的分子动力学讲义 (Dissemination).


Laboratoire International Associé
Unité mixte de recherche n°7565
Université de Lorraine, B.P. 70239
54506 Vandoeuvre-lès-Nancy Cedex, France


Phone: +33.(0)
Fax: +33.(0)
How to reach us