A comparison of seven fast but approximate methods to compute the free energy of deprotonation for amino acids in aqueous solution

In recent years, a variety of methods based on statistical mechanics have b een successfully applied to calculate free energy differences of chemical r eactions from molecular simulation. The accuracy and computational efficien cy vary strongly between these methods. Seven approximate but fast methods to calculate free energy differences are compared in terms of accuracy and efficiency with the accurate but expensive thermodynamic integration method as reference, using 28 protonation and deprotonation reactions of aspartic acid in aqueous solution as test cases. At least two simulations are requi red to obtain an accurate free energy difference between two states of the system. Both, the averaged one-step perturbation method and the linear resp onse method yield the most accurate results, while the latter method shows the fastest convergence.