Oscillatory dynamics arising from competitive inhibition and multisite phosphorylation.

Area of Science:

• Biochemistry
• Systems Biology
• Computational Biology

Background:

• Growing observations of oscillating protein levels (e.g., p53, NFkB) in eukaryotic signaling pathways.
• Renewed interest in the mechanisms underlying these biological oscillations.
• Previous computational work suggests multisite phosphorylation can exhibit bistability.

Purpose of the Study:

• To investigate oscillatory dynamics arising from bistable multisite phosphorylation cycles.
• To describe two distinct network architectures that generate such oscillations.
• To illustrate the versatility of bistable multisite phosphorylation networks.

Main Methods:

• Theoretical modeling of multisite phosphorylation cycles.
• Analysis of network dynamics incorporating sequestration and saturation mechanisms.
• Simulation of two specific network designs: a repression-based relaxation oscillator and a two-cycle ring oscillator.

Main Results:

• Demonstrated that multisite phosphorylation cycles can exhibit bistability due to enzyme sequestration and saturation.
• Characterized a relaxation oscillator where phosphorylated protein represses kinase production.
• Characterized a ring oscillator in a two-cycle cascade with feedback inhibition.

Conclusions:

• Bistable multisite phosphorylation networks provide a versatile mechanism for generating biological oscillations.
• The described network models offer insights into the dynamics of signaling pathways with oscillating proteins.
• These findings contribute to understanding the fundamental principles of biological network behavior.