Ligand Binding General Framework

The study of receptor-ligand binding is one of the most important applications of free energy simulations [1]. To approach this problem theoretically, one must first partition the conformational space into bound and unbound states. There is no unique way to do this, but in practical situations there is often a natural choice. The equilibrium binding constant is 

To relate the standard binding free energy to free energies that can be obtained from simulations, we use 

Many applications are only concerned with binding free energy differences. Comparing the binding of two ligands, L and L , to the receptor R, we have 

the standard state concentration cancels from the double free energy difference. The calculation can be done by mutating L to L both in the complex and in solution (the horizontal legs of Fig. 12.1). 

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