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Network motifs – recurring circuitry components in biological systems
Citation:
Cheng, W., S. Bhattacharya, R. Conolly, AND Q. Zhang. Network motifs – recurring circuitry components in biological systems. Computational Systems Biology and Dose Response Modeling Meeting, East lansing, Michigan, May 15 - 17, 2017.
Impact/Purpose:
The workshop will cover dynamical systems modeling techniques for quantitative investigation of how biological systems respond to perturbations at the cellular level.
Description:
Environmental perturbations, elicited by chemicals, dietary supplements, and drugs, can alter the dynamics of the molecular circuits and networks operating in cells, leading to multiple disease endpoints. Multi-component signal transduction pathways and gene regulatory circuits underpin integrated cellular responses to perturbations. A recurring set of network motifs serve as the basic building blocks of these molecular signaling networks. We believe that mechanistic evidence for the existence of thresholds has to come from studying the underlyin biological networks as nonlinear dynamical systems. We computationally analyzed the abilities of several intracellular biochemical network motifs to generate threshold responses. These motifs include proportional and integral feedback control. We further focus on ultrasensitive response motifs (URMs) that amplify small percentage changes in the input signal into larger percentage changes in the output response. URMs generally possess a sigmoid input–output relationship that is steeper than the Michaelis–Menten type of response and is often approximated by the Hill function. Six types of URMs can be commonly found in intracellular molecular networks and each has a distinct kinetic mechanism for signal amplification. These URMs are: (i) positive cooperative binding, (ii) homo-multimerization, (iii) multistep signaling, (iv) molecular titration, (v) zero-order covalent modification cycle and (vi) positive feedback. Multiple URMs can be combined to generate highly switch-like responses. Serving as basic signal amplifiers, these URMs are essential for molecular circuits to produce complex nonlinear dynamics, including multi-stability, robust adaptation and oscillation. These dynamic properties are in turn responsible for higher-level cellular behaviors, such as cell fate determination, homeostasis and biological rhythm.