A control theoretic framework for modular analysis and design of biomolecular networks

Control theory has been instrumental for the analysis and design of a number of engineering systems, including aerospace and transportation systems, robotics and intelligent machines, manufacturing chains, electrical, power, and information networks. In the past several years, the ability of de novo creating biomolecular networks and of measuring key physical quantities has come to a point in which quantitative analysis and design of biological systems is possible. While a modular approach to analyze and design complex systems has proven critical in most control theory applications, it is still subject of debate whether a modular approach is viable in biomolecular networks. In fact, biomolecular networks display context-dependent behavior, that is, the input/output dynamical properties of a module change once this is part of a network. One cause of context dependence, similar to what found in many engineering systems, is retroactivity, that is, the effect of loads applied on a module by downstream systems. In this paper, we focus on retroactivity and review techniques, based on nonlinear control and dynamical systems theory, that we have developed to quantify the extent of modularity of biomolecular systems and to establish modular analysis and design techniques

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

Implementing nonlinear feedback controllers using DNA strand displacement reactions

We show how an important class of nonlinear feedback controllers can be designed using idealized abstract chemical reactions and implemented via DNA strand displacement (DSD) reactions. Exploiting chemical reaction networks (CRNs) as a programming language for the design of complex circuits and networks, we show how a set of unimolecular and bimolecular reactions can be used to realize input-output dynamics that produce a nonlinear quasi sliding mode (QSM) feedback controller. The kinetics of the required chemical reactions can then be implemented as enzyme-free, enthalpy/entropy driven DNA reactions using a toehold mediated strand displacement mechanism via Watson-Crick base pairing and branch migration. We demonstrate that the closed loop response of the nonlinear QSM controller outperforms a traditional linear controller by facilitating much faster tracking response dynamics without introducing overshoots in the transient response. The resulting controller is highly modular and is less affected by retroactivity effects than standard linear designs

Computational analysis of protein interaction networks for infectious diseases

Infectious diseases caused by pathogens, including viruses, bacteria and parasites, pose a serious threat to human health worldwide. Frequent changes in the pattern of infection mechanisms and the emergence of multidrug resistant strains among pathogens have weakened the current treatment regimen. This necessitates the development of new therapeutic interventions to prevent and control such diseases. To cater to the need, analysis of protein interaction networks (PINs) has gained importance as one of the promising strategies. The present review aims to discuss various computational approaches to analyse the PINs in context to infectious diseases. Topology and modularity analysis of the network with their biological relevance, and the scenario till date about host-pathogen and intra-pathogenic protein interaction studies were delineated. This would provide useful insights to the research community thereby enabling them to design novel biomedicine against such infectious diseases

LQG Control and Sensing Co-Design

We investigate a Linear-Quadratic-Gaussian (LQG) control and sensing co-design problem, where one jointly designs sensing and control policies. We focus on the realistic case where the sensing design is selected among a finite set of available sensors, where each sensor is associated with a different cost (e.g., power consumption). We consider two dual problem instances: sensing-constrained LQG control, where one maximizes control performance subject to a sensor cost budget, and minimum-sensing LQG control, where one minimizes sensor cost subject to performance constraints. We prove no polynomial time algorithm guarantees across all problem instances a constant approximation factor from the optimal. Nonetheless, we present the first polynomial time algorithms with per-instance suboptimality guarantees. To this end, we leverage a separation principle, that partially decouples the design of sensing and control. Then, we frame LQG co-design as the optimization of approximately supermodular set functions; we develop novel algorithms to solve the problems; and we prove original results on the performance of the algorithms, and establish connections between their suboptimality and control-theoretic quantities. We conclude the paper by discussing two applications, namely, sensing-constrained formation control and resource-constrained robot navigation.Comment: Accepted to IEEE TAC. Includes contributions to submodular function optimization literature, and extends conference paper arXiv:1709.0882