Why Proteins are Big: Length Scale Effects on Equilibria and Kinetics

Area of Science:

• Biophysics
• Physical Chemistry
• Polymer Science

Background:

• Proteins are typically described using small molecule thermodynamics and kinetics, which can obscure their unique properties.
• This small molecule approach hinders understanding why proteins have evolved to be large polymers.
• Many protein behaviors appear paradoxical when viewed solely through a small molecule lens.

Purpose of the Study:

• To re-evaluate protein thermodynamics and kinetics by considering them as polymers.
• To explain paradoxical protein behaviors like weak, selective binding and large kinetic changes from small perturbations.
• To elucidate the role of polymer dimensions and solvent interactions in protein behavior.

Main Methods:

• Applying polymer physical chemistry principles to protein structure and function.
• Analyzing entropic and enthalpic contributions in protein systems.
• Utilizing concepts like multivalent binding and the chelate effect.

Main Results:

• Protein properties arise from their polymer dimensions, including entropic rubber elasticity.
• Entropic contributions are primarily within the polymer, while enthalpy comes from small molecule binding.
• Polymer perspective clarifies weak, selective binding and enzyme sensitivity to perturbations.

Conclusions:

• Viewing proteins as polymers provides clarity on their structure, function, and thermodynamics.
• Polymer physics explains phenomena like low denaturation energies and complex kinetic substates.
• This approach integrates length-scale dependent thermodynamic measurements and solvent effects for a comprehensive understanding.