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


CONCLUSIONS
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.
Kut
Carmen
C
Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. ckut1@jhmi.edu
Golkhou
Vahid
V
Bader
Joel S
JS
D000818:Animals; D001683:Biological Clocks / Q000502:physiology*; D002940:Circadian Rhythm / Q000502:physiology*; D003198:Computer Simulation; D025461:Feedback, Physiological / Q000502:physiology*; D008954:Models, Biological