Retroactivity Attenuation in Bio-Molecular Systems Based on Timescale Separation

As with several engineering systems, bio-molecular systems display impedance-like effects at interconnections, called retroactivity. In this paper, we propose a mechanism that exploits the natural timescale separation present in bio-molecular systems to attenuate retroactivity. Retroactivity enters the dynamics of a bio-molecular system as a state dependent disturbance multiplied by gains that can be very large. By virtue of the system structure, retroactivity can be arbitrarily attenuated by internal system gains even when these are much smaller than the gains multiplying retroactivity terms. This result is obtained by employing a suitable change of coordinates and a nested application of the singular perturbation theorem on the finite time interval. As an application example, we show that two modules extracted from natural signal transduction pathways have a remarkable capability of attenuating retroactivity, which is certainly desirable in any (engineered or natural) signal transmission system.United States. Air Force Office of Scientific Research (AFOSR Award FA9550-09-1-0211

Model reduction for a class of singularly perturbed stochastic differential equations

A class of singularly perturbed stochastic differential equations (SDE) with linear drift and nonlinear diffusion terms is considered. We prove that, on a finite time interval, the trajectories of the slow variables can be well approximated by those of a system with reduced dimension as the singular perturbation parameter becomes small. In particular, we show that when this parameter becomes small the first and second moments of the reduced system's variables closely approximate the first and second moments, respectively, of the slow variables of the singularly perturbed system. Chemical Langevin equations describing the stochastic dynamics of molecular systems with linear propensity functions including both fast and slow reactions fall within the class of SDEs considered here. We therefore illustrate the goodness of our approximation on a simulation example modeling a well known biomolecular system with fast and slow processes.United States. Air Force Office of Scientific Research (Grant FA9550-14-1-0060)National Institute of General Medical Sciences (U.S.) (Grant P50 GMO9879

How retroactivity impacts the robustness of genetic networks

This paper studies how retroactivity impacts the robustness of gene transcription networks against parameter perturbations. By employing the linearization technique and the real stability radius, we provide comparisons of the robustness between gene transcription networks with retroactivity and ones without retroactivity. Both numerical and analytical results show that retroactivity tends to decrease such robustness. This finding in turn implies that modular genetic networks tend to be more robust against parameter perturbations.National Science Foundation (U.S.) (NSF-CCF-I058127

Retroactivity attenuation through signal transduction cascades

This paper considers the problem of attenuating retroactivity, that is, the effect of loads in biological networks and demonstrates that signal transduction cascades incorporating phosphotransfer modules have remarkable retroactivity attenuation ability. Uncovering the biological mechanisms for retroactivity attenuation is relevant in synthetic biology to enable bottom-up modular composition of complex circuits. It is also important in systems biology for deepening our current understanding of natural principles of modular organization. In this paper, we perform a combined theoretical and computational study of a cascade system comprising two phosphotransfer modules, ubiquitous in eukaryotic signal transduction, when subject to load from downstream targets. Employing singular perturbation on the finite time interval, we demonstrate that this system implements retroactivity attenuation when the input signal is sufficiently slow. Employing trajectory sensitivity analysis about nominal parameters that we have identified from in vivo data, we further demonstrate that the key parameters for retroactivity attenuation are those controlling the timescale of the system.Grant FA9550-12-1-0219National Science Foundation (U.S.). Division of Computing and Communication Foundations (1058127

Modularity in signaling systems

Modularity is a property by which the behavior of a system does not change upon interconnection. It is crucial for understanding the behavior of a complex system from the behavior of the composing subsystems. Whether modularity holds in biology is an intriguing and largely debated question. In this paper, we discuss this question taking a control system theory view and focusing on signaling systems. In particular, we argue that, despite signaling systems being constituted of structural modules, such as covalent modification cycles, modularity does not hold in general. As in any engineering system, impedance-like effects, called retroactivity, appear at interconnections and alter the behavior of connected modules. We further argue that while signaling systems have evolved sophisticated ways to counter-act retroactivity and enforce modularity, retroactivity may also be exploited to finely control the information processing of signaling pathways. Testable predictions and experimental evidence are discussed with their implications

Loading as a design parameter for genetic circuits

A significant problem when building complex biomolecular circuits is due to context-dependence: the dynamics of a system are altered upon changes to its context, potentially degrading the system's performance. Here, we study retroactivity, a specific type of context-dependence, by analyzing the effects of loads on a transcription factor applied by the transcription factor's target sites. In particular, we study this loading effect on the model of an activator-repressor oscillator, a widely studied motif in synthetic and systems biology. Our analysis indicates that strong activation and weak repression are key for a stable limit cycle. Repression can be effectively weakened by adding load to the repressor, while activation can be effectively weakened by adding load to the activator. Therefore, loading the repressor can be employed as a design parameter to establish a stable limit cycle. In contrast, loading the activator is deleterious to the clock

Optimal design of phosphorylation-based insulation devices

We seek to minimize both the retroactivity to the output and the retroactivity to the input of a phosphorylation-based insulation device by finding an optimal substrate concentration. Characterizing and improving the performance of insulation devices brings us a step closer to their successful implementation in biological circuits, and thus to modularity. Previous works have mainly focused on attenuating retroactivity effects to the output using high substrate concentrations. This, however, worsens the retroactivity to the input, creating an error that propagates back to the output. Employing singular perturbation and contraction theory tools, this work provides a framework to determine an optimal substrate concentration to reach a tradeoff between the retroactivity to the input and the retroactivity to the output.Grant FA9550-12-1-021

An N-stage Cascade of Phosphorylation Cycles as an Insulation Device for Synthetic Biological Circuits

Single phosphorylation cycles have been found to have insulation device abilities, that is, they attenuate the effect of retroactivity applied by downstream systems and hence facilitate modular design in synthetic biology. It was recently discovered that this retroactivity attenuation property comes at the expense of an increased retroactivity to the input of the insulation device, wherein the device slows down the signal it receives from its upstream system. In this paper, we demonstrate that insulation devices built of cascaded phosphorylation cycles can break this tradeoff allowing to attenuate the retroactivity applied by downstream systems while keeping a small retroactivity to the input. In particular, we show that there is an optimal number of cycles that maximally extends the linear operating region of the insulation device while keeping the desired retroactivity properties, when a common phosphatase is used. These findings provide optimal design strategies of insulation devices for synthetic biology applications.NIH P50 GMO98792 gran