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 (GBOBC1); (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.
ASJC Scopus subject areas
- Physical and Theoretical Chemistry
- Surfaces, Coatings and Films
- Materials Chemistry