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Analytical approximations for the amplitude and period of a relaxation oscillator.

ABSTRACT: BACKGROUND: Analysis and design of complex systems benefit from mathematically tractable models, which are often derived by approximating a nonlinear system with an effective equivalent linear system. Biological oscillators with coupled positive and negative feedback loops, termed hysteresis or relaxation oscillators, are an important class of nonlinear systems and have been the subject of comprehensive computational studies. Analytical approximations have identified criteria for sustained oscillations, but have not linked the observed period and phase to compact formulas involving underlying molecular parameters. RESULTS: We present, to our knowledge, the first analytical expressions for the period and amplitude of a classic model for the animal circadian clock oscillator. These compact expressions are in good agreement with numerical solutions of corresponding continuous ODEs and for stochastic simulations executed at literature parameter values. The formulas are shown to be useful by permitting quick comparisons relative to a negative-feedback represillator oscillator for noise (10x less sensitive to protein decay rates), efficiency (2x more efficient), and dynamic range (30 to 60 decibel increase). The dynamic range is enhanced at its lower end by a new concentration scale defined by the crossing point of the activator and repressor, rather than from a steady-state expression level. CONCLUSION: Analytical expressions for oscillator dynamics provide a physical understanding for the observations from numerical simulations and suggest additional properties not readily apparent or as yet unexplored. The methods described here may be applied to other nonlinear oscillator designs and biological circuits.

SUBMITTER: Kut C

PROVIDER: S-EPMC2657111 | biostudies-literature | 2009

REPOSITORIES: biostudies-literature

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Analytical approximations for the amplitude and period of a relaxation oscillator.

Kut Carmen C Golkhou Vahid V Bader Joel S JS

BMC systems biology 20090114

<h4>Background</h4>Analysis and design of complex systems benefit from mathematically tractable models, which are often derived by approximating a nonlinear system with an effective equivalent linear system. Biological oscillators with coupled positive and negative feedback loops, termed hysteresis or relaxation oscillators, are an important class of nonlinear systems and have been the subject of comprehensive computational studies. Analytical approximations have identified criteria for sustaine ...[more]

PMID: 19144174

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Project description:BackgroundOne of the distinctive features of biological oscillators such as circadian clocks and cell cycles is robustness which is the ability to resume reliable operation in the face of different types of perturbations. In the previous study, we proposed multiparameter sensitivity (MPS) as an intelligible measure for robustness to fluctuations in kinetic parameters. Analytical solutions directly connect the mechanisms and kinetic parameters to dynamic properties such as period, amplitude and their associated MPSs. Although negative feedback loops are known as common structures to biological oscillators, the analytical solutions have not been presented for a general model of negative feedback oscillators.ResultsWe present the analytical expressions for the period, amplitude and their associated MPSs for a general model of negative feedback oscillators. The analytical solutions are validated by comparing them with numerical solutions. The analytical solutions explicitly show how the dynamic properties depend on the kinetic parameters. The ratio of a threshold to the amplitude has a strong impact on the period MPS. As the ratio approaches to one, the MPS increases, indicating that the period becomes more sensitive to changes in kinetic parameters. We present the first mathematical proof that the distributed time-delay mechanism contributes to making the oscillation period robust to parameter fluctuations. The MPS decreases with an increase in the feedback loop length (i.e., the number of molecular species constituting the feedback loop).ConclusionsSince a general model of negative feedback oscillators was employed, the results shown in this paper are expected to be true for many of biological oscillators. This study strongly supports that the hypothesis that phosphorylations of clock proteins contribute to the robustness of circadian rhythms. The analytical solutions give synthetic biologists some clues to design gene oscillators with robust and desired period.

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Analytical approximations for the amplitude and period of a relaxation oscillator.

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Analytical approximations for the amplitude and period of a relaxation oscillator.

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