A comprehensive kinetic model for ternary complex catalysis

Ternary-complex directed enzyme catalysis underlies a vast array of biological processes and several clinical therapies including growth hormones, interferon, and heparin. Recently, interest in ternary catalysis drugs has increased significantly with the rapid expansion of research new technologies such as bispecific antibodies and proteolysis targeting chimeras (PROTAC’s). Here, we derive a general model for ternary complex catalysis that defines the timescales of these diverse processes in familiar terms from classical enzyme theory. This was accomplished by solving for the maximum velocity (Vmax) and adapting an under-appreciated strategy within Michaels and Menten’s original publication: integration of the velocity equation. Critically, these equations are simple, conceptually accessible, and enables rapid estimation timescales that are consistent with a wide range of published literature. Finally, we have combined these equations with “big data” from new thermodynamic and kinetic databases to build interactive online tools that enable non-computational investigators to graphically simulate their own systems: • https://douglasslab.com/Btmax_kinetics/ Overall, this work is part of a general trend to reconceptualize pharmacodynamics from classical binding equilibria (e.g. Langmuir-Hill equation) to a kinetic processes with a characteristic timescale.