Protein-ligand binding free energy calculation by the Smooth Reaction Path Generation (SRPG) Method.

We developed a new molecular dynamics simulation method for protein-ligand binding free energy calculation in an explicit water model. This method consists of three steps: (1) generation of a compound dissociation path starting from a stable protein-compound complex structure, (2) calculation of the free energy surface along the dissociation path, and (3) calculation of the free energy surface of a small area around the protein-compound complex structure, which is a free energy minimum. The protein-compound binding free energy is estimated from the information obtained by the above three steps. This method was applied to a small system, a 18-crown-6 ether with its ligand ion, and a realistic system consisting of a target protein with its inhibitor. This approximation worked well; the protein-inhibitor dissociation was successfully performed, and the binding free energies were calculated.