COMPUTATIONAL ALCHEMY TO CALCULATE ABSOLUTE PROTEIN-LIGAND BINDING FREE-ENERGY

The ability to reliably compute accurate protein-ligand binding affini ties is crucial to understanding protein-ligand recognition and to str ucture-based drug design.;A ligand's binding affinity is specified by its absolute binding free energy, Delta G(bind), the free energy diffe rence between the bound and unbound states. To compute accurate free e nergy differences by free energy perturbation (FEP), ''alchemical'' ra ther than physical processes are usually simulated by molecular dynami cs simulations so as to minimize the perturbation to the system. Here, we report a novel ''alchemistic'' application of the FEP methodology involving a large perturbation. By mutating a ligand with 11 non-hydro gen atoms into six water molecules in the binding site of a protein, w e computed a Delta G(bind) within 3 kJ/mol of the experimental value. This is the first successful example of the computation of Delta G(bin d) for a protein:ligand pair with full treatment of the solvent degree s of freedom.