Association

Association refers to the binding interaction between a free ligand (L) and a free receptor or other target protein (P) to create a complex between the two species (LP):

The rate of association is governed by an association rate constant, referred to here as k_on, but often also as k₁.  The units of k_on for the binding interaction between one ligand molecule and one target protein are M^-1s^-1. The meaning of k_on is not intuitively apparent; the numerical value indicates the number of association events that could occur between a single protein target and a ligand present at a concentration of 1 M, in one second, if the protein was always available to associate with a ligand. This abstract idea is easier to visualise if the reciprocal of the association rate constant is thought of as the time required to complete one association event. For example, if k_on is 1×10⁷ M^-1s^-1, then a single protein target molecule could form a complex with ligand (present at 1 M) 10⁷ times every second, or alternatively, one association event is completed every 10^-7 seconds.

The actual rate of the forward reaction (creating LP) is found by multiplying the concentrations of the two reactants, L and P, by the association rate constant. Thus, rate = k_on[L][P]. The rate calculated in this way indicates the initial rate of increase in concentration of the LP complex. However, as the concentrations of the reactants are depleted, the association rate slows (often rapidly), and a plot of [LP] versus time would be exponential.

Popular convention has been that for many biological interactions between small molecule ligands and target proteins, values for k_on lie within an order of magnitude in either direction from 1×10⁷ M^-1s^-1 – in other words, between 1×10⁶ M^-1s^-1 and 1×10⁸ M^-1s^-1. As such, differences between binding affinities of different ligands for a protein target have been considered as due largely to differences in dissociation constants. However, it is now accepted that association rate constants lie across a very wide range and that effects on drug behaviour may be quite profound.

Further details and examples may be found under the manual entry for affinity.