Exploring Folding Aspects of Monomeric Superoxide Dismutase

Area of Science:

• Biochemistry
• Structural Biology
• Neuroscience

Background:

• Amyotrophic lateral sclerosis (ALS) is linked to mutations and metal-free (apo) forms of Cu-Zn Human Superoxide Dismutase (SOD1).
• SOD1 aggregation is a proposed mechanism in ALS pathogenesis.
• Understanding SOD1 folding and stability is crucial for ALS research.

Purpose of the Study:

• To investigate the impact of metal ions on SOD1 protein folding pathways and stability.
• To explore how the absence of metal ions influences SOD1's free-energy barrier and folding kinetics.
• To correlate simplified model findings with existing detailed studies on SOD1 structure and ALS.

Main Methods:

• Utilized a structure-based computational model.
• Modified interaction energy between amino acids in the metal-binding site.
• Analyzed differences in folding pathways and kinetics between apo and holo SOD1 forms.

Main Results:

• The presence of metal ions lowers the free-energy barrier for SOD1 folding.
• Metal ions alter the folding pathway, facilitating the attainment of the native state.
• Absence of metal ions significantly reduces the stability of the native SOD1 state.
• Disulfide bond absence decreases native structure stability but minimally affects the transition state.

Conclusions:

• Metal ion binding is critical for efficient SOD1 folding and native state stability.
• The findings support the role of metal-ion dysregulation in SOD1 misfolding and ALS.
• The disulfide bond appears to form late in the SOD1 folding process.