Assessing the performance of MM/PBSA and MM/GBSA methods. 5. Improved docking performance using high solute dielectric constant MM/GBSA and MM/PBSA rescoring

Abstract

With the rapid development of computational techniques and hardware, more rigorous and precise theoretical models have been used to predict the binding affinities of a large number of small molecules to biomolecules. By employing continuum solvation models, the MM/GBSA and MM/PBSA methodologies achieve a good balance between low computational cost and reasonable prediction accuracy. In this study, we have thoroughly investigated the effects of interior dielectric constant, molecular dynamics (MD) simulations, and the number of top-scored docking poses on the performance of the MM/GBSA and MM/PBSA rescoring of docking poses for three tyrosine kinases, including ABL, ALK, and BRAF. Overall, the MM/PBSA and MM/GBSA rescoring achieved comparative accuracies based on a relatively higher solute (or interior) dielectric constant (i.e. ε = 2, or 4), and could markedly improve the 'screening power' and 'ranking power' given by Autodock. Moreover, with a relatively higher solute dielectric constant, the MM/PBSA or MM/GBSA rescoring based on the best scored docking poses and the multiple top-scored docking poses gave similar predictions, implying that much computational cost can be saved by considering the best scored docking poses only. Besides, compared with the rescoring based on the minimized structures, the rescoring based on the MD simulations might not be completely necessary due to its negligible impact on the docking performance. Considering the much higher computational demand of MM/PBSA, MM/GBSA with a high solute dielectric constant (ε = 2 or 4) is recommended for the virtual screening of tyrosine kinases.

Identification of phenoxyacetamide derivatives as novel DOT1L inhibitors via docking screening and molecular dynamics simulation

“…This tool calculates components of binding free energy using the Molecular Mechanic/Poisson-Boltzmann Surface Area (MM/PBSA) method [59][60][61][62][63], and it can also be used to investigate the binding associations between the protein and the ligand by decomposing the total binding free energy into each residue. Besides, it provides several optional types of parameters for calculating the polar Poisson−Boltzmann (PB) equation [64] was solved due to our highly charged system.…”

Computationally unraveling how ceritinib overcomes drug-resistance mutations in ALK-rearranged lung cancer

“…Furthermore, the popular molecular mechanics-generalized Born/surface area (MM-GBSA) method was developed to assess the free energies of protein-protein and protein-ligand interactions [16,17]. In the present study, computational studies including MD simulations, MM-GBSA binding free energy calculations, per-residue free-energy decomposition, principal component analysis (PCA), and domain cross-correlation analysis were performed on wild-type and mutated ALKceritinib complexes (I1171T, L1196M, S1206Y, and G1269A ALK mutants were investigated).…”

Exploring the influence of hyperthermophilic protein Ssh10b on the stability and conformation of RNA by molecular dynamics simulation

“…The MM-GB/SA approach [25][26][27][28][29][30][31] supported by the AMBER 12 [37] were carried out to calculate the binding free energies for Ssh10b-RNA complex. A total of 1000 snapshots were extracted from the MD trajectory of each simulation to calculate the Ssh10b-RNA binding free energy.…”

“…At the beginning, MD simulations were carried out at 6 temperatures (300, 350, 375, 400, 450, and 500 K) to obtain dynamics structural information. And then, MM-GB/SA approach [25][26][27][28][29][30][31] was applied to calculate the binding free energies and understand the interaction details of Ssh10b-RNA complex. We obtain some details about the contribution of individual residues by decomposing the total binding free energy.…”