  The binding of a ligand molecule to a protein is often accompanied by
conformational changes of the protein. A central question is whether the ligand
induces the conformational change (induced-fit), or rather selects and
stabilizes a complementary conformation from a pre-existing equilibrium of
ground and excited states of the protein (selected-fit). We consider here the
binding kinetics in a simple four-state model of ligand-protein binding. In
this model, the protein has two conformations, which can both bind the ligand.
The first conformation is the ground state of the protein when the ligand is
off, and the second conformation is the ground state when the ligand is bound.
The induced-fit mechanism corresponds to ligand binding in the unbound ground
state, and the selected-fit mechanism to ligand binding in the excited state.
We find a simple, characteristic difference between the on- and off-rates in
the two mechanisms if the conformational relaxation into the ground states is
fast. In the case of selected-fit binding, the on-rate depends on the
conformational equilibrium constant, while the off-rate is independent. In the
case of induced-fit binding, in contrast, the off-rate depends on the
conformational equilibrium, while the on-rate is independent. Whether a protein
binds a ligand via selected-fit or induced-fit thus may be revealed by
mutations far from the protein's binding pocket, or other "perturbations" that
only affect the conformational equilibrium. In the case of selected-fit, such
mutations will only change the on-rate, and in the case of induced-fit, only
the off-rate.
