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