European Molecular Biology Laboratory, 69012 Heidelberg, Germany
Abstract:
The ability to reliably compute accurate protein-ligand binding affinities
is crucial to understanding protein-ligand recognition and to structure-based
drug design. A ligand's binding affinity is specified by its absolute binding
free energy, DGbind, the free energy
difference between the bound and unbound states. To compute accurate free
energy differences by free energy perturbation (FEP), "alchemical" rather
than physical processes are usually simulated by molecular dynamics 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-hydrogen atoms into six water molecules
in the binding site of a protein, we computed a DGbind
within 3 kJ/mol of the experimental value. This is the first successful
example of the computation of DGbind
for a protein-ligand pair with full treatment of the solvent degrees of
freedom.
J. Am. Chem. Soc. (1998) 120, 2710-2713.