Theory on the Design Principles of Protein Molecular Oscillatory Machines

Area of Science:

• Biophysics
• Computational Biology
• Biochemistry

Background:

• Multistep biomolecular processes, like enzymatic reactions and transcription factor DNA binding, require precise coordination of sequential binding events.
• Core protein oscillators that alternate between conformational substates are proposed to manage these sequential bindings.
• The feasibility of achieving efficient binding choreography without external energy input remains an open question.

Purpose of the Study:

• To theoretically investigate the requirements for designing the core oscillator of molecular machines.
• To analyze oscillatory binding patterns arising from protein domain thermal fluctuations in different folding scenarios (two-state vs. downhill).

Main Methods:

• Theoretical modeling of protein domain flexibility and marginal stability.
• Analysis of conformational dynamics, including unfolding pathways (two-state and downhill).
• Investigation of oscillatory binding patterns driven by thermal fluctuations.

Main Results:

• Neither pure downhill nor pure two-state folding protein domains can function as effective core oscillators.
• Downhill folding speeds conformational transitions but results in fleeting binding-competent substate residence times.
• Two-state folding provides ample binding time but leads to slow, decorrelated transitions.

Conclusions:

• Optimal efficiency is achieved when oscillators can rapidly interconvert between downhill and two-state scenarios in response to environmental cues.
• This alternating downhill vs. two-state interconversion mechanism may be a natural design principle for efficient, energy-independent coordination of multistep processes.
• The model aligns with transcription factor genome searches and predicts experimental rates for the pyruvate dehydrogenase complex.