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Native topology determines force-induced unfolding pathways in globular proteins
1Department of Chemistry and Biochemistry and Institute for Physical Science and Technology, University of Maryland, College Park, MD 20742, USA. klimov@glue.umd.edu
Summary
Stretching proteins like titin and tenascin reveals how their folded domains unfold. This study predicts protein unfolding forces and pathways using only native structure, applicable to various protein types.
Area of Science:
- Biophysics
- Structural Biology
- Computational Biology
Background:
- Elastic proteins such as titin and tenascin possess tandem repeats of folded domains with beta-sandwich architecture.
- Single-molecule manipulation techniques are used to study the mechanical unfolding of these proteins.
Purpose of the Study:
- To develop a predictive model for protein unfolding forces and pathways based solely on native state structure.
- To investigate the role of native topology in force-induced protein unfolding.
Main Methods:
- Stretching of model protein sequences (S1 and S2) with four-stranded beta-barrel topology.
- Steered Langevin dynamics simulations.
- Analysis of force-temperature (f,T) phase diagrams.
Main Results:
- Unfolding forces and pathways can be predicted using only the native state structure.
- The unfolding mechanism (all-or-none vs. intermediate) is determined by the native topology.
- The model accurately predicts unfolding events in immunoglobulin and fibronectin type III domains, and coiled-coil spectrin.
Conclusions:
- Native protein topology dictates force-induced unfolding pathways and forces.
- The predictive approach offers insights into protein mechanical stability and refolding.
- This method can be extended to predict unfolding in a wider range of protein structures and under varying denaturant concentrations.