How proteins' negative cooperativity emerges from entropic optimisation of versatile collective fluctuations

Area of Science:

• Biophysics
• Biochemistry
• Computational Biology

Background:

• Allostery enables nonlocal signaling in proteins through entropy balance of collective thermal modes.
• Mechanisms underlying negative cooperativity in allosteric systems remain incompletely understood.
• Conformational changes are not always necessary for allosteric effects.

Purpose of the Study:

• To elucidate the mechanisms generating negative cooperativity in protein complexes.
• To investigate how effector binding influences allosteric signaling.
• To explore the role of entropy and collective modes in allostery.

Main Methods:

• Utilized an elastic-network model for small protein complexes.
• Modeled effector binding by locally altering interaction strengths.
• Employed a coupled harmonic oscillator approach to analyze eigenmodes and frequencies.
• Traced changes in eigenmodes, frequencies, and statistical weights through successive binding events.

Main Results:

• Demonstrated that altering oscillator couplings is key to achieving both positive and negative allostery.
• Showed that binding-modified couplings generate unique eigenmodes for each binding state.
• Identified nonuniform shifts in collective-mode frequencies as crucial for allosteric regulation.
• Revealed an enhanced optimizability linked to a detailed phase map of allosteric behaviors.

Conclusions:

• The study provides a mechanistic understanding of negative cooperativity in allosteric systems.
• Altered inter-oscillator couplings, rather than conformational changes, are central to allosteric regulation.
• The findings offer insights into the design principles of allosteric proteins and drug development.