∆Gbind calculation is crucial in drug design and virtual screening based on docking. Several calculation methods for ∆Gbind have been developed, ranging from a computationally rigorous thermodynamic path to a less complicated end point method. The former method includes thermodynamic integral method (TI) and free energy perturbation method (FEP), while linear interaction energy (LIE), the molecular-mechanics and generalized Born with surface area method (MM/PB(GB)SA) are endpoint methods. MM/PB(GB)SA are widely used in the calculation of receptor-ligand binding free energy. MM-GBSA and MM-PBSA are the two most popular known endpoint methods in SBDD which use implicit solvent models to calculate solvent molecules, and apply dielectric continuum models to obtain the electrostatic component of solvation energy. The ∆Gbind of MM-PB(GB)SA can be calculated using the formula:
∆Gbind = ∆Gpolar + ∆Gnonpolar
∆GSolv is the solvation energies which is the sum of the polar (∆Gpolar) and non-polar (∆Gnonpolar) contributions of solvation. Solvation analysis is one of the most important tasks in chemical and biological modeling. At Alfa Chemistry, we use the GB model to calculate polar solvation. Nonpolar solvation dynamics of a nonpolar diatomic solute can be followed via nonequilibrium molecular dynamics (MD) simulation. And the non-polar contribution of ligands and proteins is calculated based on the size of the solvent accessible surface area.
Figure 1. Scheme of the alchemical thermodynamic cycle used to obtain the absolute binding free energies. (Aldeghi, M.; et al. 2016)
- At Alfa Chemistry, two strategies are commonly applied in MM-GBSA and MM-PBSA calculations: the three-track scheme and the single-track scheme.
- In addition to the choice of strategy, we have optimized several factors that can affect the calculation of MM/PB(GB)SA, including the length of the simulation time, the choice of force field, the dielectric constant of the solute, the solvent model, and the net charge of the system.
- We have modified the GB/SA model to study the nonpolar contribution to the solvation energy.
- Our scientists can fold and assemble helical membrane peptides by combining this implicit model for the solvent/bilayer environment with advanced computational sampling methods, like replica-exchange molecular dynamics.
- We are capable of exploring the role of biological membranes in affecting the conformational changes and predicting the configuration of transmembrane helical bundles.
Nonpolar Solvation Energy Calculation Process
- First, extract frames from a single or multiple complex molecular dynamics simulation, allowing comparison between multiple trajectories.
- Second, split the complex frames in the single components including complex, protein and ligand.
- Third, the nonpolar solvation energy value is calculated with a linear relation to the solvent-accessible surface area according to the empirical surface area method:
∆Gpolar = ∆Gsurface = γA + B
- Our well-designed method is found to perform well in each of these cases and is anticipated to be useful in the study of folding and assembly of membrane proteins as well as in structure refinement and modeling of membrane proteins where a limited number of experimental observables are available.
- Our predictions of the nonpolar solvation energies are in an excellent agreement with experimental data, which supports the validity of the proposed nonpolar solvation model.
- We can define the solvent-solute boundary via the variation of the nonpolar solvation free energy obtained by MM/PB(GB)SA.
Our nonpolar solvation energy calculation with MM/PB(GB)SA services remarkably reduce the cost, promote further experiments, and accelerate the process of drug design for customers worldwide. Our personalized and all-around services will satisfy your innovative study demands. If you are interested in our services, please don't hesitate to contact us. We are glad to cooperate with you and witness your success!
- Aldeghi, M.; et al. Accurate calculation of the absolute free energy of binding for drug molecules. Chemical Science. 2016, 7(1): 207-218.