Facile: a command-line network compiler for systems biology

<p>Abstract</p> <p>Background</p> <p>A goal of systems biology is the quantitative modelling of biochemical networks. Yet for many biochemical systems, parameter values and even the existence of interactions between some chemical species are unknown. It is therefore important to be able to easily investigate the effects of adding or removing reactions and to easily perform a bifurcation analysis, which shows the qualitative dynamics of a model for a range of parameter values.</p> <p>Results</p> <p>We present Facile, a Perl command-line tool for analysing the dynamics of a systems biology model. Facile implements the law of mass action to automatically compile a biochemical network (written as, for example, <monospace>E + S <-> C</monospace>) into scripts for analytical analysis (Mathematica and Maple), for simulation (XPP and Matlab), and for bifurcation analysis (AUTO). Facile automatically identifies mass conservations and generates the reduced form of a model with the minimum number of independent variables. This form is essential for bifurcation analysis, and Facile produces a C version of the reduced model for AUTO.</p> <p>Conclusion</p> <p>Facile is a simple, yet powerful, tool that greatly accelerates analysis of the dynamics of a biochemical network. By acting at the command-line and because of its intuitive, text-based input, Facile is quick to learn and can be incorporated into larger programs or into automated tasks.</p

Cross-Talk between Signaling Pathways Can Generate Robust Oscillations in Calcium and cAMP

BACKGROUND:To control and manipulate cellular signaling, we need to understand cellular strategies for information transfer, integration, and decision-making. A key feature of signal transduction is the generation of only a few intracellular messengers by many extracellular stimuli. METHODOLOGY/PRINCIPAL FINDINGS:Here we model molecular cross-talk between two classic second messengers, cyclic AMP (cAMP) and calcium, and show that the dynamical complexity of the response of both messengers increases substantially through their interaction. In our model of a non-excitable cell, both cAMP and calcium concentrations can oscillate. If mutually inhibitory, cross-talk between the two second messengers can increase the range of agonist concentrations for which oscillations occur. If mutually activating, cross-talk decreases the oscillation range, but can generate 'bursting' oscillations of calcium and may enable better filtering of noise. CONCLUSION:We postulate that this increased dynamical complexity allows the cell to encode more information, particularly if both second messengers encode signals. In their native environments, it is unlikely that cells are exposed to one stimulus at a time, and cross-talk may help generate sufficiently complex responses to allow the cell to discriminate between different combinations and concentrations of extracellular agonists

Identification of IKr Kinetics and Drug Binding in Native Myocytes

Determining the effect of a compound on IKr is a standard screen for drug safety. Often the effect is described using a single IC50 value, which is unable to capture complex effects of a drug. Using verapamil as an example, we present a method for using recordings from native myocytes at several drug doses along with qualitative features of IKr from published studies of HERG current to estimate parameters in a mathematical model of the drug effect on IKr. IKr was recorded from canine left ventricular myocytes using ruptured patch techniques. A voltage command protocol was used to record tail currents at voltages from −70 to −20 mV, following activating pulses over a wide range of voltages and pulse durations. Model equations were taken from a published IKr Markov model and the drug was modeled as binding to the open state. Parameters were estimated using a combined global and local optimization algorithm based on collected data with two additional constraints on IKrI–V relation and IKr inactivation. The method produced models that quantitatively reproduce both the control IKr kinetics and dose dependent changes in the current. In addition, the model exhibited use and rate dependence. The results suggest that: (1) the technique proposed here has the practical potential to develop data-driven models that quantitatively reproduce channel behavior in native myocytes; (2) the method can capture important drug effects that cannot be reproduced by the IC50 method. Although the method was developed for IKr, the same strategy can be applied to other ion channels, once appropriate channel-specific voltage protocols and qualitative features are identified

The response of the system with positive or mutually activating interactions between cAMP and calcium.

<p>a A bifurcation diagram for calcium as a function of activated PLC when activated AC is at 0.17 M. Symbols are the same as <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0007189#pone-0007189-g002" target="_blank">Fig. 2</a>. PD indicates a period-doubling bifurcation. Example time courses of calcium and cAMP are shown when activated PLC is at 0.2 M, 0.28 M, 0.31 M, and 0.36 M. Bursting oscillations appear for intermediate activated PLC concentrations. The amplitude of the oscillations increases and decreases as activated PLC increases, and oscillations gradually disappear. b The frequency of the cAMP and calcium oscillations as a function of both activated AC and PLC concentrations. c The amplitude of the calcium oscillations. d The amplitude of the cAMP oscillations.</p

A schematic of the G, or cAMP, and G, or calcium, pathways.

<p>a Agonist (the triangle) binding to receptor activates a G protein, , which in turn activates an effector protein, . For simplicity, the G protein is always bound to the receptor, and we show explicitly neither G and G nor the deactivation of the G protein. b The G pathway. The effector protein is the isoform of phospholipase C. When activated, PLC cleaves the phospholipid PIP into membrane-bound DAG and cytosolic IP. High IP concentrations cause the release of calcium ions from the endoplasmic reticulum. PKC when bound by calcium is recruited to the membrane by DAG and becomes activated. c The G pathway. The effector protein is adenylyl cyclase which synthesizes cAMP from ATP when activated. d The increased concentrations of cytosolic cAMP activate PKA by binding to its inhibitory domain.</p

Values used for the parameters in the model.

<p>Values used for the parameters in the model.</p