Reply to Douglass and Spiegel: A suite of mathematical solutions to describe ternary complex formation and their application to targeted protein degredation by heterobifunctional ligands

Abstract

Calculating equilibrium concentration of a ternary complex for a given total ligand concentration (1, 2) and predicting the ternary complex concentration in equilibrium with a given free ligand concentration (3) are two totally different questions that lead to clearly distinct mathematical solutions. Even though an exact solution to one question can be an approximate answer to the other, the latter approach (3) is consistent with a long-established tradition of analyzing equilibrium behavior of binding reactions: the equilibrium dissociation constants, Kds, that are used in both approaches are defined by the free, not total, ligand concentration at equilibrium, and the universally adopted equation for a bimolecular binding reaction, B = Bmax ∗ [L]/([L] + Kd), is also a function of free ligand concentration at equilibrium.