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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).
Again, various restraining potentials can be used to enhance the sampling and convergence.
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