MM-PBSA: Challenges and opportunities

Abstract

Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) is arguably the most popular method for free binding energy prediction since it is considerably more accurate than docking or scoring methods, but considerably less demanding than Free Energy Perturbation (FEP). In this review, the most important challenges and opportunities associated to this method were addressed and evaluated. The following conclusions were obtained: accuracy of MM-PBSA calculations still strongly depends on the settings used for the prediction, the conditions in which Molecular Dynamics simulations (MD) are made, the conditions from which the experimental data are obtained, it depends on the presence of the complex structure and this method has also shown to be unable to provide accurate results for charged molecules. On the other hand, it presents many opportunities since many improvements were based on MM-PBSA calculations such as Single Amino Acid Mutation based change in Binding free Energy (SAAMBE), bootstrap, dampened Molecular Mechanics Poisson-Boltzmann Surface Area (dMM-PBSA), a high throughput method called g_mmpbsa, a method based on both MM-PBSA calculations and a scoring function, force fields for inhomogeneous protein specific environments and many other new ways of improving the accuracy of this promising method. This study intends to clarify what are the major trends in this field and thus contribute to increase MM-PBSA's applicability and efficiency.