Abstract
At present, the calculated binding free energy obtained using the molecular mechanics/Poisson-Boltzmann (Generalized-Born) surface area (MM/PB(GB)SA) method is overestimated due to the lack of knowledge of suitable interior dielectric constants in the simulation on the interaction of Human Immunodeficiency Virus (HIV-1) protease systems with inhibitors. Therefore, the impact of different values of the interior dielectric constant and the entropic contribution when using the MM/PB(GB)SA method to calculate the binding free energy was systemically evaluated. Our results show that the use of higher interior dielectric constants (1.4–2.0) can clearly improve the predictive accuracy of the MM/PBSA and MM/GBSA methods, and computational errors are significantly reduced by including the effects of electronic polarization and using a new highly efficient interaction entropy (IE) method to calculate the entropic contribution. The suitable range for the interior dielectric constant is 1.4–1.6 for the MM/PBSA method; within this range, the correlation coefficient fluctuates around 0.84, and the mean absolute error fluctuates around 2 kcal/mol. Similarly, an interior dielectric constant of 1.8–2.0 produces a correlation coefficient of approximately 0.76 when using the MM/GBSA method. In addition, the entropic contribution of each individual residue was further calculated using the IE method to predict hot-spot residues, and the detailed binding mechanisms underlying the interactions of the HIV-1 protease, its inhibitors, and bridging water molecules were investigated. In this study, the use of a higher interior dielectric constant and the IE method can improve the calculation accuracy of the HIV-1 system.
Highlights
Our results show that the use of higher interior dielectric constants (1.4–2.0) can clearly improve the predictive accuracy of the MM/PBSA and MM/GB module of the MM/PBSA (GBSA) methods, and computational errors are significantly reduced by including the effects of electronic polarization and using a new highly efficient interaction entropy (IE) method to calculate the entropic contribution
It is apparent that root mean square deviations (RMSDs) for most of the ten systems in the protein-specific charge (PPC) force field were smaller than those in the AMBER force field, which indicates that the PPC force field can provide a reliable and dynamically stable structure. This result demonstrates the important effects of electronic polarization in MD simulations and indicates that the use of the PPC force field was appropriate for our subsequent experiments
10 ns MD simulations were carried out in both nonpolarized (AMBER) and polarized (PPC) force fields to investigate the impact of higher interior dielectric constants when using the MM/PB(GB)SA method to calculate the binding free energy of HIV-1 proteaseinhibitor complexes
Summary
We compared the dynamical property between the PPC force field and two versions AMBER02 and AMBER12 polarizable force fields and found that the PPC force field gave more stable structures than the other two polarizable force fields.[13,14] This method successfully incorporates electrostatic polarization effects, and its advantages over the traditional force field have been shown in a series of studies.[8–11,15–18]. Due to the lack of a reliable and efficient method for calculating entropic changes, many previous studies neglected the entropic contribution to the binding free energy when applying the MM/PBSA method, which resulted in some inaccurate results.[37–45]. Due to its simplicity and practicality, the IE method has been widely used by our own group as well as other researchers to calculate many different types of binding free energies and explain important interaction mechanisms in biological systems.[41,56–62]. Due to its lack of effect on protein motion and polarization, the interior dielectric constant (dielectric in the solute) is usually set to 1 when calculating the electrostatic energy
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