Binding Free Energy Calculation


The calculation of the standard (absolute) binding free energy of a small ligand to a receptor macromolecule is one of the most important problem in computational biophysics. In recent years, there have been important advances in methodologies that enable one to carry out such calculations with a reasonable accuracy (see Deng and Roux, 2009 for a recent review).
One approach to compute the binding free energy of a small molecule ligand is to use alchemical FEP/MD. (Deng and Roux, 2006). The free energy associated with the interactions is split into repulsive, dispersive and electrostatic contributions. To accelerate convergence and avoid instability in simulations, a soft-core potential is used on the repulsive interaction. Various restraining potentials can be used to enhance the sampling and take into account of the standard state. The effect of these restraint potentials are removed with extra simulation steps. For a typical drug-like ligand, restraint potentials on the ligand translation, rotation and conformation degrees of freedom are required. The ligand conformation (measured by RMSD from bound conformation) can be calculated using umbrella sampling.
Another approach to compute the binding free energy of a small molecule ligand is to use a PMF as a function of the ligand-receptor separation (Woo and Roux, 2004). This work was extended to incorporate a protein conformational PMF in a paper in Nature Structural & Molecular Biology (Lau and Roux, 2011). Again, various restraining potentials can be used to enhance the sampling and convergence.

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