New tutorial on protein-ligand binding using free-energy calculations
Binding of a short proline-rich peptide to the src-homology domain 3 of tyrosine kinase Abl
The Theoretical and Computational Biophysics Group (TCBG), NIH Center for Macromolecular Modeling and Bioinformatics, is pleased to announce the release of the Protein:ligand Standard Binding Free Energies: A Tutorial for Alchemical and Geometrical Transformations tutorial. As described in the tutorial abstract:
"This tutorial sets out to demonstrate the application of numerical simulations to the calculation of the standard binding free energy of a protein:ligand complex. To a large extent, computation of standard binding free energies remains a daunting theoretical challenge on account of the considerable variations in conformational, translational and orientational entropies that accompany the association of the substrate to the host protein and is not easily captured by conventional molecular-dynamics simulations. Sampling these entropic contributions is addressed here, following two distinct routes, an alchemical one and a geometrical one, wherein restraining potentials have been introduced to act on the collective variables that define the conformation of the ligand and its relative position and orientation with respect to the protein. The methodology is illustrated by the well-documented example of a small, proline-rich peptide, referred to as p41, associating to the Src homology 3 domain of a tyrosine kinase with a standard binding free energy of -7.94 kcal/mol. Considering the difficulties that current additive force fields face to describe organic ligands, e.g., drugs, the choice of an all-peptide-based molecular assembly is particularly fitting, allowing the reader to focus primarily on the methodology and the sampling."
The tutorial consists of a text in pdf format and files used in the tutorial, available at the free energy tutorial page, and via the links below:
Protein:ligand Standard Binding Free Energies: A Tutorial for Alchemical and Geometrical Transformations (pdf, 614k) (required tutorial files [.tar.gz, 14.4M])
The tutorial is written by Dr. James Gumbart, School of Physics, Georgia Institute of Technology; Dr. Benoit Roux, Department of Biochemistry and Molecular Biology, Gordon Center for Integrative Science, The University of Chicago; and Dr. Christophe Chipot, Centre National de la Recherche Scientifique, Laboratoire International Associe CNRS-UIUC, Universite de Lorraine. TCBG thanks the authors for their tutorial contribution!
