Calculation of Standard Binding Free Energies: Aromatic Molecules in the T4 Lysozyme L99A Mutant

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Abstract
Calculations of the binding free energy of various nonpolar aromatic ligands with the L99A mutant of T4 lysozyme using molecular dynamics (MD) simulation are presented. To ensure better convergence, biasing potentials are used to restrain the ligand orientation and center-of-mass movement relative to the binding site when the ligand is decoupled from its environment in the binding pocket. The bias introduced by the restraint potentials is removed once the ligand fully interacts with the rest of the system and the calculated binding free energy is independent of the applied restraints. To decrease the computational cost, the simulations are generated with a reduced system in which protein and water atoms within a 15 Å-radius sphere around the ligand are included explicitly, while the rest of the system is treated with the generalized solvent boundary potential (GSBP). For all the ligands, the precision of the calculated free energy is less than 0.5 kcal/mol. For small nonpolar ligands such as benzene, toluene, and ethylbenzene, the calculated binding free energies are within 1.1 kcal/mol of the experimental values. For larger ligands, the computed binding free energies are slightly more favorable than the experimental values. The nonbinding polar molecule, phenol, has a calculated binding free energy of −0.88 kcal/mol. The simulation protocol presented here provides a way to calculate the binding free energy of small molecules to receptors at moderate computational cost.