How Well Does the Extended Linear Interaction Energy Method Perform in Accurate Binding Free Energy Calculations?

With continually increased computer power, molecular mechanics force field-based approaches, such as the endpoint methods of molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) and molecular mechanics generalized Born surface area (MM-GBSA), have been routinely applied in both drug lead identification and optimization. However, the MM-PB/GBSA method is not as accurate as the pathway-based alchemical free energy methods, such as thermodynamic integration (TI) or free energy perturbation (FEP). Although the pathway-based methods are more rigorous in theory, they suffer from slow convergence and computational cost. Moreover, choosing adequate perturbation routes is also crucial for the pathway-based methods. Recently, we proposed a new method, coined extended linear interaction energy (ELIE) method, to overcome some disadvantages of the MM-PB/GBSA method to improve the accuracy of binding free energy calculation. In this work, we have systematically assessed this approach using in total 229 protein–ligand complexes for eight protein targets. Our results showed that ELIE performed much better than the molecular docking and MM-PBSA method in terms of root-mean-square error (RMSE), correlation coefficient (R), predictive index (PI), and Kendall’s τ. The mean values of PI, R, and τ are 0.62, 0.58, and 0.44 for ELIE calculations. We also explored the impact of the length of simulation, ranging from 1 to 100 ns, on the performance of binding free energy calculation. In general, extending simulation length up to 25 ns could significantly improve the performance of ELIE, while longer molecular dynamics (MD) simulation does not always perform better than short MD simulation. Considering both the computational efficiency and achieved accuracy, ELIE is adequate in filling the gap between the efficient docking methods and computationally demanding alchemical free energy methods. Therefore, ELIE provides a practical solution for the routine ranking of compounds in lead optimization.