Binding free-energy calculation of an ion-peptide complex by constrained dynamics

Binding free energy is the most important physical parameter that describes the binding affinity of a receptor-ligand complex. Conventionally, it was obtained based on the thermodynamic cycle or alchemical reaction. These strategies have been widely used, but they would be problematic if the receptors and/or ligands have large conformational changes during the binding processes. In this paper, we present a way to calculate the binding free energy: constrained dynamics along a fragmental and high-dimensional transition path. This method directly considers unbound states in the simulation. The application to the calmodulin loop-calcium complexes shows that it is practical and the calculated relative binding affinities are in good agreement with experimental results.