Protein unfolding under force: crack propagation in a network

Area of Science:

• Biophysics
• Computational Biology
• Materials Science

Background:

• Understanding protein mechanical unfolding is crucial for molecular biology and drug design.
• Existing models often struggle to capture the complex pathways of protein denaturation.

Purpose of the Study:

• To investigate the mechanical unfolding of 12 diverse proteins using a novel constraint-based model.
• To determine if a crack propagation analogy can accurately describe protein unfolding pathways.

Main Methods:

• An all-atom constraint-based model representing proteins as cross-linked polypeptides.
• Harmonic inequality constraints model interactions like hydrogen bonds and salt bridges.
• Iterative network overloading simulates unfolding, analogous to crack propagation.

Main Results:

• The model successfully generated stereochemically acceptable unfolding pathways.
• For 9 out of 12 proteins, the predicted pathways closely matched experimental and molecular dynamics data.
• The crack propagation analogy proved effective in describing dominant unfolding routes.

Conclusions:

• Mechanical protein unfolding can be effectively modeled as a crack propagation process in a constraint network.
• This computational approach offers a powerful tool for predicting protein behavior under mechanical stress.
• The findings provide insights into protein stability and denaturation mechanisms.