CL-FEP: An End-State Free Energy Perturbation Approach

摘要

The Central Limit Free Energy Perturbation (CL-FEP) approach, based on the Free Energy Perturbation (FEP) theory and the Central Limit (CL) theorem, allows evaluating the FEP identity directly from the energy samples of the end states of a system transformation. In CL-FEP, energies obtained from explicit solvent simulations are used to estimate the absolute free energy change. No fitted parameters are introduced in our implementation, and no stratification is needed to obtain accurate free energy evaluations. We first illustrate the applicability of CL-FEP in four dissimilar benchmark systems from host-guest to proteins-peptide complexes, for which the deviation from the experimental values was below 1 kcal/mol. Next, we extended the validation to three sets of complexes comprising 25 host-guest and protein-ligand systems. There, the mean absolute error of the free energy changes calculated with CL-FEP is between 1.1 and 1.4 kcal/mol among the different sets, which is in the range of accuracy of the most reliable free energy approaches applied to these systems. CL-FEP is an unbiased free energy change estimator that also profits from a bootstrapping algorithm, which makes the evaluation of convergence and confidence an inherent component of the procedure. Finally, we developed CLFEP.pl, an automatic tool to compute free energy changes directly from the energy output of standard molecular dynamics simulations.