Cooperativity in Cellular Biochemical Processes: Noise-Enhanced Sensitivity, Fluctuating Enzyme, Bistability with Nonlinear Feedback, and Other Mechanisms for Sigmoidal Responses

Cooperativity in classical biophysics originates from molecular interactions; nonlinear feedbacks in biochemical networks regulate dynamics inside cells. Using stochastic reaction kinetic theory, we discuss cooperative transitions in cellular biochemical processes at both the macromolecular and the cellular levels. We show that fluctuation-enhanced sensitivity (stochastic focusing) shares an essential feature with the transition in a bistable system. The same theory explains zeroth-order ultrasensitivity with temporal cooperativity. Dynamic cooperativity in fluctuating enzyme (i.e., dynamic disorder), stochastic focusing, and the recently proposed stochastic binary decision all have a shared mechanism: They are generalizations of the hyperbolic response of Michaelis-Menten kinetics x/(K + x), with fluctuating K or stochastic x. Sigmoidal dependence on substrate concentration necessarily yields affinity amplification for competing ligands; both sigmoidal response and affinity amplification exhibit a square law. We suggest two important characteristics in a noise: its multimodal distribution structure and its temporal irreversibility. The former gives rise to self-organized complexity, and the latter contains useful, albeit hidden, free energy that can be utilized for biological functions. There could be structures and energy in biochemical fluctuations.