Calculation of Absolute ProteinLigand Binding Constants with the Molecular Dynamics Free Energy Perturbation Method

Reliable first-principles calculations of protein—ligand binding constants can play important roles in the study and characterization of biological recognition processes and applications to drug discovery. A detailed procedure for such a calculation is outlined in this chapter. The methodology is computationally implemented using the molecular dynamics sampling of relevant configurational spaces and free energy perturbation techniques. The procedure is illustrated with the model system of the phosphotyrosine peptide binding to the Src SH2 domain.