A diversity of methods have been developed to perform accurate calculation of binding free energy. Among these methods, free energy perturbation (FEP), linear interaction energy (LIE) and thermodynamic integral (TI) are both accurate and mature approaches. However, a large amount of calculation is required for all of them which is not suitable for biological macromolecular systems. Poisson-Boltzmann or generalized Born and surface area continuum solvation (MM/PBSA and MM/GBSA) methods are popular approaches based on molecular dynamics simulations of the receptor-ligand complex to estimate the free energy of the binding of small ligands to biological macromolecules. MM-PB(GB)SA is a powerful method of post-processing the molecular dynamics trajectory to estimate the binding free energy, in which the solvent is treated as a uniform continuous medium. This method is developed based on the force field and the implicit continuum model, and many equilibrium trajectories frames are averaged to consider the effects of temperature.
Principle of MM/PB(GB)SA
MM/PB(GB)SA calculates binding free energy by splitting the binding free energy into molecular mechanics term and solvation energy term. It calculates the difference between the binding free energy of two solvated molecules in the bound and unbound states or compares the free energy of different solvation conformations of the same molecule.
Figure 1. Comparison of binding free energies computed using 1traj MMPBSA based ESMACS protocol with experimental data. (Wright, D. W.; et al. 2020)
Features of MM/PB(GB)SA
- Modular nature
- Do not require calculations on a training set
- Reproduce and rationalize experimental findings
- Improve the results of virtual screening and docking
Binding Free Energy Calculation Process with MM/PB(GB)SA
- Select topology file and trajectory file
- Divide receptor and ligand
- Set the parameter of salt concentration
- Output binding free energy
- Output energy decomposition data
- Plot the energy contribution
Alfa Chemistry have applied many attempts to improve the accuracy of calculation results by employing multiple algorithms:
- Our scientists have individually tested and improved six energy terms to perform better binding free energy calculation using multiple models or calculation methods:
1. The electrostatic term: Polarizable potentials, multipole expansions or QM calculations.
2. The polar solvation term: The three-dimensional reference site interaction model (3D-RISM) and the quantum mechanics (QM)-based polarized continuum model (PCM).
3. The non-polar solvation term: The SASA model and 3D-RISM methods.
4. The entropy term: Minimization of the free receptor and the free ligand from the minimized structure of the complex.
- Replacing MM with QM
We replace the MM energies with a solvated semi-empirical QM (SQM) estimate to establish a QM/MM-PBSA approach, in which the ligand is treated with QM and the rest with MM.
1. We use MP2/cc-pVTZ QM calculations to replace the MM part to calculate all chemical groups.
2. Our scientists apply linear-scaling density functional theory (DFT) calculations to ligand binding.
3. Alfa Chemistry also supports ab initio methods.
- Our method helps to understand the specific energy contribution of each amino acid to ligand binding, including VDW, solvation energy, electrostatic energy, etc.
- We have rich experience in the dynamic simulation of biological macromolecules, enabling us to perform a rapid free energy calculation.
- The binding free energy obtained from MM/PB(GB)SA can be used to clarify the mechanism and guide the structural modification.
Our binding free 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!
- Wright, D. W.; et al. Application of the ESMACS Binding Free Energy Protocol to a Multi-Binding Site Lactate Dehydogenase A Ligand Dataset. Advanced Theory and Simulations. 2020, 3(1).