Development and Evaluation of MM/GBSA Based on a Variable Dielectric GB Model for Predicting Protein–Ligand Binding Affinities

Abstract

In structure-based drug design (SBDD), the molecular mechanics generalized Born surface area (MM/GBSA) approach has been widely used in ranking the binding affinity of small molecule ligands. However, an accurate estimation of protein–ligand binding affinity still remains a challenge due to the intrinsic limitation of the standard generalized Born (GB) model used in MM/GBSA. In this study, we proposed and evaluated the MM/GBSA approach based on a variable dielectric generalized Born (VDGB) model using residue-type-based dielectric constants. In the VDGB model, different dielectric values were assigned for the three types of protein residues, and the magnitude of the dielectric constants for residue types follows this order: charged ≥ polar ≥ nonpolar. We found that MM/GBSA based on a VDGB model (MM/GBSAVDGB) with an optimal dielectric constant of 4.0 for the charged residues and 1.0 for the noncharged residues together with a net-charge-dependent dielectric value for ligands achieved better predictions as judged by Pearson’s correlation coefficient than the standard MM/GBSA with a uniform solute dielectric constant of 4.0 for the training set of 130 protein–ligand complexes. The prediction on the test set with 165 protein–ligand complexes also validated the better performance of MM/GBSAVDGB. Moreover, this method exhibited potential in predicting the relative binding free energies for multiple ligands against the same target. Furthermore, we found that rational truncation of protein residues far from the binding site can significantly speed up the MM/GBSAVDGB calculations, while it almost does not influence the prediction accuracy. Therefore, it is feasible to implement the system-truncated MM/GBSAVDGB as a scoring function for SBDD.

Thermodynamic Dissection of the Intercalation Binding Process of Doxorubicin to dsDNA with Implications of Ionic and Solvent Effects

“…The MM-GBSA method has been successfully demonstrated recently in diverse systems, including protein−protein, 57 DNA−protein, 58 ligand−protein, 59 and drug−DNA 60 interactions, and has also been used to study the binding of DOX to different macromolecules. 46,61−63 The BFEs of our proposed models are calculated by utilizing three-trajectory protocol (3TP) of the MM-GBSA method using long-timescale MD simulations in the context of an explicit solvent TIP3P water model with a neutralized total charge of the system.…”

“…The MM-GBSA method we adopted has many advantages: it is more accurate than most empirical scoring approaches of molecular docking and less computationally demanding than free alchemical energy methods; it can be modified to analyze the BFE with respect to the binding stages in the intercalation process of drugs, and it can break down the BFE to their thermodynamic components and can be further decomposed into per-residue energetic contributions, which make it possible to capture the local dominant interactions between DOX and the BPs of dsDNA including contributions from individual BPs that are located near the DOX intercalation site. The MM-GBSA method has been successfully demonstrated recently in diverse systems, including protein–protein, DNA–protein, ligand–protein, and drug–DNA interactions, and has also been used to study the binding of DOX to different macromolecules. ,− …”

Discovery of a species‐specific novel antifungal compound against Fusarium graminearum through an integrated molecular modeling strategy

“…32 The parameters for the VD-MM/GBSA calculation were reported in a previous study. 31,33 The binding free energies were calculated as an average of the results from three trajectories.…”

“…The sander module in Amber was modified correspondingly to read the revised AMBER system topology in which a new block of atomic dielectric constants was added 32 . The parameters for the VD‐MM/GBSA calculation were reported in a previous study 31,33 . The binding free energies were calculated as an average of the results from three trajectories.…”

Theoretical study of myriocin‐binding mechanism targeting serine palmitoyltransferase

“…Where G complex , G protein, and G ligand are the prime energies of the optimized complex, free receptor, and free ligand, respectively (Li et al, 2019;Singh & Silakari, 2018;Wang et al, 2020;Wang, Sun, et al, 2019;Wang, Yang, et al, 2021;Zhu et al, 2019aZhu et al, , 2019bZhu et al, , 2019cZhu et al, , 2020bZhu et al, , 2021cZhu et al, , 2021dZhu, Yu, et al, 2020).…”