Assessing the performance of MM/PBSA and MM/GBSA methods. 3. The impact of force fields and ligand charge models

Abstract

Here, we systematically investigated how the force fields and the partial charge models for ligands affect the ranking performance of the binding free energies predicted by the Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) and Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) approaches. A total of 46 small molecules targeted to five different protein receptors were employed to test the following issues: (1) the impact of five AMBER force fields (ff99, ff99SB, ff99SB-ILDN, ff03, and ff12SB) on the performance of MM/GBSA, (2) the influence of the time scale of molecular dynamics (MD) simulations on the performance of MM/GBSA with different force fields, (3) the impact of five AMBER force fields on the performance of MM/PBSA, and (4) the impact of four different charge models (RESP, ESP, AM1-BCC, and Gasteiger) for small molecules on the performance of MM/PBSA or MM/GBSA. Based on our simulation results, the following important conclusions can be obtained: (1) for short time-scale MD simulations (1 ns or less), the ff03 force field gives the best predictions by both MM/GBSA and MM/PBSA; (2) for middle time-scale MD simulations (2-4 ns), MM/GBSA based on the ff99 force field yields the best predictions, while MM/PBSA based on the ff99SB force field does the best; however, longer MD simulations, for example, 5 ns or more, may not be quite necessary; (3) for most cases, MM/PBSA with the Tan's parameters shows better ranking capability than MM/GBSA (GB(OBC1)); (4) the RESP charges show the best performance for both MM/PBSA and MM/GBSA, and the AM1-BCC and ESP charges can also give fairly satisfactory predictions. Our results provide useful guidance for the practical applications of the MM/GBSA and MM/PBSA approaches.