Enlightening the blind spot of the Michaelis–Menten rate law: The role of relaxation dynamics in molecular complex formation

The century-long Michaelis–Menten rate law and its modifications in the modeling of biochemical rate processes stand on the assumption that the concentration of the complex of interacting molecules, at each moment, rapidly approaches an equilibrium (quasi-steady state) compared to the pace of molecular concentration changes. Yet, in the case of actively time-varying molecular concentrations with transient or oscillatory dynamics, the deviation of the complex profile from the quasi-steady state becomes relevant. A recent theoretical approach, known as the effective time-delay scheme (ETS), suggests that the delay from the relaxation time of molecular complex formation contributes to the substantial breakdown of the quasi-steady state assumption. Here, we systematically expand this ETS and inquire into the comprehensive roles of relaxation dynamics in complex formation. Through the modeling of rhythmic protein–protein and protein–DNA interactions and the mammalian circadian clock, our analysis reveals the effect of the relaxation dynamics beyond the time delay, which extends to the dampening of changes in the complex concentration with a reduction in the oscillation amplitude compared to the quasi-steady state. Interestingly, the combined effect of the time delay and amplitude reduction shapes both qualitative and quantitative oscillatory patterns such as the emergence and variability of the mammalian circadian rhythms. These findings highlight the downside of the routine assumption of quasi-steady states and enhance the mechanistic understanding of rich time-varying biomolecular processes.