Ligand-binding Pocket into proteins

PL shows a possible titration curve of a ligand that does not initially fit into the ATP-binding pocket. The ligand binds to the protein building an intermediate state. This intermediate state is in a conformational equilibrium with the complex. The titration ends with two separate peaks. This ensemble of titration curves is incompatible with a key/bolt mechanism described in (a), (c) The model P- -L-o-P +L< PL depicts possible titration curves of a weak binder to an alternative conformation of the kinase (e.g., the putative DFG-in/DFG-out). A conformational equilibrium already exists in the free form. The ligand binds only to one of the conformations. The titration starts with two peaks. One of them constantly decreases while the other signal broadens and then arises in a new sharp peak. 

This indicates how favorable it is to take the ligand out of solution and into the protein binding pocket. 

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