Efficient and Accurate Free Energy Calculations on Trypsin Inhibitors.

Several combinations of free energy calculation methods have been applied to determine the relative free energies of binding between eight para-substituted benzamidines in complex with the serine protease trypsin. With the aim to improve efficiency and maintain accuracy, the linear response approximation (LRA), linear interaction energy (LIE) and third power fitting (TPF) are combined with the one-step perturbation (OSP) to determine the polar and apolar contributions to the free energy, respectively. It is shown that the combination TPF/OSP gives the most accurate results and is 4.5 times more efficient than the rigorous thermodynamic integration (TI). By projecting the electrostatic preorganization energy from the OSP simulations, an increase in efficiency of a factor 7.5 can even be achieved. Loss of accuracy with respect to the TI data is limited to 3.9 and 5.6 kJ/mol, respectively, making it an attractive approach for lead optimization programs in drug research.