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bioRxiv · 10.1101/2023.09.14.557821

Sensitivity and Frequency Response of Biochemical Cascades

Kochen, M. A.·Hellerstein, J. L.·Sauro, H. M.
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Abstract

AO_SCPLOWBSTRACTC_SCPLOWSignal transduction from a cells surface to cytoplasmic and nuclear targets takes place through a complex network of interconnected pathways. Phosphorylation cycles are common components of many pathways and may take the form of a multi-layered cascade of cycles or incorporate species with multiple phosphorylation sites that effectively create a sequence of cycles with increasing states of phosphorylation. This work focuses on the frequency response and sensitivity of such systems, two properties that have not been thoroughly examined. Starting with a singularly phosphorylated single-cycle system, we compare the sensitivity to perturbation at steady-state across a range of input signal strengths. This is followed by a frequency response analysis focusing on the gain and associated bandwidth. Next, we consider a two-layer cascade of single phosphorylation cycles and focus on how the two cycles interact to produce various effects on the bandwidth and damping properties. Then we consider the (ultra)sensitivity of a doubly phosphorylated system, where we describe in detail first-order ultrasensitivity, a unique property of these systems, which can be blended with zero-order ultrasensitivity to create systems with relatively constant gain over a range of signal input. Finally, we give an in-depth analysis of the sensitivity of an n-phosphorylated system.

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Kochen, M. A., Hellerstein, J. L., Sauro, H. M.. 2023-09-17. Sensitivity and Frequency Response of Biochemical Cascades. https://doi.org/10.1101/2023.09.14.557821

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