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Assay Development for High Content Quantification of Sod1 Mutant Protein Aggregate Formation in Living Cells
Published on: October 4, 2017
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Interaction between dimer interface residues of native and mutated SOD1 protein: a theoretical study
1Department of Physics, Bharathiar University, Coimbatore, 641 046, India.
Summary
Mutations in copper-zinc superoxide dismutase 1 (SOD1) disrupt dimer stability, leading to protein misfolding and aggregation. Loss of hydrogen bonds at the dimer interface reduces stability in mutated SOD1 forms.
Area of Science:
- Biochemistry
- Structural Biology
- Enzymology
Background:
- Copper-zinc superoxide dismutase 1 (SOD1) is crucial for scavenging superoxide radicals.
- Over 100 mutations in SOD1 are linked to disease, often affecting its homodimeric structure.
- Maintaining SOD1's dimeric state is essential for its stability and enzymatic function.
Purpose of the Study:
- To investigate how mutations, particularly those outside the dimer interface, affect SOD1's dimer stability.
- To understand the role of non-covalent interactions, specifically hydrogen bonds, in maintaining SOD1's dimeric structure.
- To analyze the impact of mutations on SOD1's aggregation and misfolding tendencies.
Main Methods:
- Molecular dynamics simulations were employed to study hydrogen bond interactions in native and mutated SOD1 (apo- and holo-states).
- Quantum mechanical studies using M052X/6-31G(d) level of theory were performed on dimer interface residues.
- Analysis of charge transfer in N-H···O interactions within the dimer interface.
Main Results:
- Mutations not directly at the dimer interface were found to destabilize the SOD1 dimer.
- A loss of hydrogen bond interactions between monomers significantly reduces the stability of mutated SOD1.
- Weakened interactions at the dimer interface lead to reduced dimerization and increased deformation energy in mutated SOD1.
Conclusions:
- The study highlights that disruptions in hydrogen bonding at the dimer interface are a primary cause of SOD1 instability in mutated forms.
- These instabilities contribute to protein misfolding and aggregation, implicating altered dimer interactions in SOD1-related pathologies.
- Understanding these molecular interactions is key to developing therapeutic strategies for SOD1-related diseases.
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