Stochastic ordering of complexoform protein assembly by genetic circuits

Area of Science:

• Proteomics and Systems Biology
• Computational Biology and Biophysics

Background:

• Top-down proteomics reveals protein complex heterogeneity, termed complexoforms.
• The role of cellular circuits in controlling complexoform distribution remains largely unknown.

Purpose of the Study:

• To investigate how cellular circuits, including gene transcription, mRNA translation, and protein transport timing, control complexoform distribution.
• To model and understand the impact of genetic circuitry and kinetic parameters on complexoform assembly.

Main Methods:

• Simulated a generic three-protein complexoform using 265 computational experiments.
• Averaged results over 1,000 stochastic simulations per experiment.
• Tested the model against the biological cellulosome system using biologically relevant rates.

Main Results:

• Gene arrangement (operon, cascade) influences complexoform composition due to protein synthesis order timing.
• Expression kinetics, protein transport, and binding rates significantly alter complexoform distribution.
• Both stochastic and transient kinetics affect complexoform assembly when expression and assembly are concurrent.

Conclusions:

• Genetic circuit architecture and kinetics are crucial determinants of complexoform distribution.
• This work provides insights into non-equilibrium processes in biological systems and has implications for synthetic biology.