Accessibility explains preferred thiol-disulfide isomerization in a protein domain
Katra Kolšek1, Camilo Aponte-Santamaría1,2,3, Frauke Gräter4,5
1Heidelberg Institute for Theoretical Studies, Heidelberg, Germany.
Scientific Reports
|August 31, 2017
Summary
Disulfide bonds in proteins can rearrange via thiol-disulfide exchange. This study reveals protein dynamics, not just reactivity, dictates exchange specificity, impacting protein stability and function.
Area of Science:
- Biochemistry
- Structural Biology
- Computational Biology
Background:
- Disulfide bonds are crucial for protein structure and stability.
- Spontaneous disulfide rearrangement via thiol-disulfide exchange is physiologically important but poorly understood.
- Molecular determinants of thiol-disulfide exchange remain largely unknown.
Purpose of the Study:
- To elucidate the molecular principles governing thiol-disulfide exchange in proteins.
- To investigate the role of protein dynamics and accessibility in disulfide rearrangement.
- To model thiol-disulfide exchange using a computational approach on a mutated immunoglobulin domain.
Main Methods:
- Employed a novel hybrid Monte Carlo and Molecular Dynamics (MC/MD) simulation scheme.
- Utilized a mutated immunoglobulin domain as a model system for protein analysis.
- Focused on proximity as a key criterion for predicting thiol-disulfide exchange events.
Main Results:
- The MC/MD method accurately predicted experimentally observed regiospecificity and selectivity of thiol-disulfide exchange.
- Protein dynamics and steric hindrance, rather than solely transition states, were identified as major factors.
- Accessibility of the disulfide bond to the attacking thiol is a critical bottleneck.
Conclusions:
- Protein dynamics and steric accessibility are key determinants of thiol-disulfide exchange specificity.
- The findings challenge the traditional focus on activation barriers alone.
- This understanding may apply to various proteins, influencing their stability and function.
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