Unveiling local and global conformational changes and allosteric communications in SOD1 systems using molecular...

Area of Science:

• Biochemistry
• Structural Biology
• Computational Biology

Background:

• Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease linked to mutations in the superoxide dismutase 1 (SOD1) enzyme.
• ALS-associated SOD1 mutations lead to protein misfolding, instability, and aggregation, but the underlying allosteric mechanisms are not fully understood.
• This knowledge gap hinders the development of targeted SOD1 inhibitors and understanding disease progression.

Purpose of the Study:

• To elucidate the allosteric mechanisms and communication pathways within SOD1.
• To investigate the impact of mutations and metallation states on SOD1 structure and dynamics.
• To identify key residues involved in SOD1 signaling and allosteric regulation.

Main Methods:

• Employed microsecond-scale unbiased molecular dynamics (MD) simulations.
• Integrated network analysis, including centrality, community, and path analyses.
• Studied SOD1 in various forms: Apo, Holo, Apo_CallA (mutant), and Holo_CallA (mutant).

Main Results:

• Unmetallated SOD1 and cysteine mutations exhibited significant structural variations in catalytic sites, impacting stability.
• Identified key residues essential for maintaining interfacial and structural stability, and enzyme catalysis via H-bond analysis.
• Dynamic motion analysis revealed more correlated atomic movements in the Holo system, with elucidated rationales for structural disparities.

Conclusions:

• The combination of extensive MD simulations and network analysis is effective for studying protein allostery.
• This approach provides insights into the atomistic details of SOD1 allosteric mechanisms.
• Findings contribute to understanding SOD1 dysfunction in ALS and developing novel therapeutic strategies.