A practical method for calculating binding free energy: Free Energy Perturbation (FEP).
Methods for high-throughput:
- First Principle Methods: molecular mechanics force field wich contains intra/intermolecular forces. No entropic contributions. Usually no interactions with solvent.
- Semiempirical Methods: the linear interaction energy (LIE) method to calculate absolute binding freee energies without sampling. Based on the linear response approximation for electrostatic forces.
- Empirical Methods: able to score ligands very rapidly. LUDI the most well known. Structural descriptors and regression methods, based both on structural and experimental binding data.
- Knowledge-based Potentials: based on interatomic preferences between atoms.
- Charge Representation: using ab initio techniques: by the integration of Coulomb's laws over the total charge distribution. Often approximated as point charges. Charge models or an electrostatic potential fitting for reproducing a number of grid points outside the Van der Waals surface of the molecule. M,any emprical methods.
- Van der Waals Radii: represent the effective size of atoms. Usually, the Lennard-Jones or 6-12 potential function is used.
- Solvent Representation: an explicit collection of individual water molecules, where each molecule is treated as a configuration of point charges. Simplest: 3, 4 or 5 charges and rigid geometry. Computational expensive. Another approach: continuum water models. Screening effect is represented by using a distance-dependent dielectric constant. Generalized-Born model and the Poisson-Boltzmann method. The nonpolar solvation free energy term is often assumed to be proportional to the SASA.
- The Sampling Problem: there are many degrees of freedom. At least the 6 deegrees for rigid docking must be sampled. Also, some limited flexibility.
- Receptor Flexibility: using soft scoring functions, allowing some overlap between the ligand and the receptor, accounting for structural uncertainties. Many other approaches.