Unfolding times for proteins in a force clamp

Area of Science:

• Biophysics
• Computational Biology
• Protein Dynamics

Background:

• Proteins are essential biological molecules whose function is often dependent on their folded structure.
• Unfolding of proteins can occur due to external forces, such as mechanical stretching.
• Understanding protein unfolding dynamics is crucial for comprehending protein function and misfolding diseases.

Purpose of the Study:

• To investigate the protein unfolding process under constant stretching force using a beta-barrel model.
• To analyze the dynamics of protein escape from its native state.
• To develop a theoretical framework explaining unfolding times across various force strengths.

Main Methods:

• Utilized a one-dimensional diffusion model for protein unfolding dynamics, parameterized by end-to-end distance.
• Employed the Smoluchowski equation to calculate escape times as first passage times on the protein's free-energy landscape.
• Analyzed unfolding dynamics under both strong (diffusive drift) and weak (thermal activation) force regimes.

Main Results:

• Protein unfolding dynamics were successfully modeled as one-dimensional diffusion across a range of forces.
• Identified a crossover in escape-time distribution from exponential (weak force) to inverse Gaussian (strong force).
• Developed a single expression for average unfolding time and variance, applicable to both weak and strong forces.

Conclusions:

• The study provides a unified theoretical framework for protein unfolding dynamics under mechanical force.
• The findings offer a potential explanation for recent experimental observations in proteins like ddFLN4 and ubiquitin.
• The diffusion-based model effectively captures the complex unfolding behavior of proteins subjected to external forces.