Gated binding of ligands to proteins

The binding of ligands to proteins often occurs at rates that approach the diffusion-controlled limit 1 . For spherical molecules with negligible interactions apart from isotropic reactivity on contact, the diffusion-controlled rate constant is K D ≡ 4π RD , where R is the distance between molecular centres at contact and D is the relative translational diffusion constant 1–3 . Deviations from this limiting rate due to interaction potentials 4,5 , hydrodynamic interactions 6,7 and static geometric features of the binding sites 8–13 have previously received much attention. Here, we point out another possible cause of such deviations, the dynamic modulation of binding site accessibility due to internal motions of the protein. Such motions may occur, for example, in proteins such as lysozyme, in which the active site cleft opens and closes in a stochastic manner 14,15 .