Proteins Breaking Bad: A Free Energy Perspective.

Area of Science:

• Biophysics
• Mechanobiology
• Biochemistry

Background:

• Protein aging can lead to mechanical dysfunction in tissues, compromising elasticity.
• Aged proteins transition from structured forms to unstructured polymers, altering their mechanical response.
• Understanding the molecular mechanisms behind protein aging is crucial for addressing age-related tissue degeneration.

Purpose of the Study:

• To elucidate the impact of oxidative aging on protein folding landscapes using a free energy model.
• To investigate the distinct contributions of polymer properties and hydrophobic collapse to protein folding under force.
• To identify the specific molecular events that lead to the loss of mechanical integrity in aged proteins.

Main Methods:

• Development of a free energy model to predict changes in protein folding landscapes.
• Utilizing Brownian dynamics simulations on the protein L octamer.
• Comparing simulations of naive and oxidatively damaged polyproteins to experimental observations.

Main Results:

• Protein folding under force comprises polymer properties and hydrophobic collapse.
• Oxidative damage irreversibly inhibits the hydrophobic collapse component of protein folding.
• Simulations accurately reproduced experimental data for both healthy and aged protein structures.

Conclusions:

• Oxidative aging fundamentally alters the free energy landscape of elastic proteins.
• The irreversible blockage of hydrophobic collapse is a key mechanism in protein aging.
• This research offers a predictive tool for understanding age-related diseases linked to protein mechanical changes.