A comprehensive kinetic model for ternary complex catalysis

Ternary-complex catalysis (TEC) plays a central role in many biological processes and underlies the mechanism of action for a growing class of clinical therapeutics, including growth hormones, interferons, heparin, bispecific antibodies, molecular glues, and PROTACs. Despite its importance, TEC remains conceptually opaque due to the complexity of its multi-body interactions and the lack of a unifying kinetic model. Here, we introduce a general and intuitive kinetic framework for TEC that extends the classic Michaelis–Menten model to ternary systems. By solving for the maximum catalytic rate (Vmax) and revisiting an often-overlooked insight from Michaelis and Menten’s original work – the integration of the velocity equation – we derive equations that are analytically simple yet conceptually powerful. These equations clarify how enzyme concentration, catalytic rate (kcat), and the weakest binding affinity (Kweak) jointly determine the reaction timescale, defined here as the half-life for conversion of the target species to the product under pre-equilibrium conditions. We validate our framework across a wide range of TEC-mediated systems, including heparin-based anticoagulants, PROTAC-mediated protein degradation, and antibody-dependent cell killing. To promote broader accessibility and application, we developed an interactive web-based tool (https://douglasslab.com/Btmax_kinetics/) that allows users to simulate catalytic timescales under real-world conditions using thermodynamic and kinetic datasets. By bridging historical theory with modern therapeutic challenges, this work provides a unifying conceptual lens and practical tools for studying and optimizing TEC-driven biology and drug action.