||Enzymes characterized by extremely efficient reaction rates are supposed to be perfect from a chemical point of view, so the rate-determining step for their second-order catalytic rate corresponds to the association of the free enzyme and the free substrate. In these cases the second order catalytic rate may be as high as 10^10 M–1s –1 and is never lower than 10^7 M–1s –1. The degree to which an enzyme reaches the diffusion limit gives some measure of how far an enzyme has evolved. The diffusion-limited encounter of molecules in solution can be calculated by the Einstein-Smoluchowski equation [ref 1 in article]. Such a rate, for two proteins approximated to spheres of 18 Å radius which associate with every contact without regard to orientation, is equal to 7 · 10^9 M–1s –1. The orientational constrains, due to steric specificity when the proteins associate, reduce the association rate constant by up to three orders of magnitude [ref 2]. Nevertheless, very high rate constants can be found for reactions between macromolecules. High association rate constants have been found for the association of barnase and barstar [ref 3], of hirudin and thrombin [ref 4], ferricytochrome c and ferrocytochrome b5 or in the association of the protein-DNA [ref 5] or proteinsubstrate [ref 6] complex.