Amyotrophic lateral sclerosis disease-related mutations disrupt the dimerization of superoxide dismutase 1 - A comparative molecular dynamics simulation study. (December 2022)

• Record Type: Journal Article
• Authors: Basith, Shaherin; Manavalan, Balachandran; Lee, Gwang
• Is Part Of: Computers in biology and medicine. Volume 151:Part B(2022)
• Publication Date: 2022-12
• Subjects: Amyotrophic lateral sclerosis -- Neurodegenerative disease -- Superoxide dismutase -- Mutations -- Molecular dynamic simulation -- Network theory -- Protein-protein interactions; Medicine -- Data processing -- Periodicals; Biology -- Data processing -- Periodicals; 610.285
• DOI: 10.1016/j.compbiomed.2022.106319
• Languages: English
• ISSNs: 0010-4825

Abstract

Abstract: More than 150 genes are involved in amyotrophic lateral sclerosis (ALS), with superoxide dismutase 1 (SOD1) being one of the most studied. Mutations in SOD1 gene, which encodes the enzyme SOD1 is the second most prevalent and studied cause of familial ALS. SOD1 is a ubiquitous, homodimeric metalloenzyme that forms a critical component of the cellular defense against reactive oxygen species. Several mutations in the SOD1 enzyme cause misfolding, dimerization instability, and increased aggregate formation in ALS. However, there is a lack of information on the dimerization of SOD1 monomers and the mechanistic underpinnings on how the pathogenic mutations disrupt the dimerization mechanism. Here, we presented microsecond-scale molecular dynamics (MD) simulations to unravel how interface-based mutations compromise SOD1 dimerization and provide mechanistic understanding into the corresponding process using WT and three interface-based mutant systems (A4V, T54R, and I113T). Structural stability analysis showed that the mutant systems displayed disparate variations in the catalytic sites which may directly alter the stability and activity of the SOD1 enzyme. Based on the dynamic network analysis and principal component analysis, it has been identified that the mutations weakened the correlated motions along the dimer interface and altered the protein conformational behavior, thus weakening the stability of dimer formation. Moreover, the simulation results identified crucial residues such as G51, D52, G114, I151, and Q153 in establishing the dimerization interaction network, which were weakened or absent in the presence of interfacial mutants. Surface potential analysis on mutant systems also displayed changes in the dimerization potential, thus showing the unfavorable dimer formation. Furthermore, network analysis identified the hotspot residues necessary for SOD1 signal transduction which were surprisingly found in the catalytic sites rather than the anticipated dimerization interface. Graphical abstract: Image 1 Highlights: Strong inter- and intra-correlated motions and weaker anti-correlated motions in SOD1 WT increase the dimer formation. Higher binding energy and larger total dimerization area of SOD1 WT assist the dimer interface to form a compact network. Strong H-bond interactions and high structural complementarity in the dimer interface preserve interfacial stability in WT. Synchronized behavior of WT monomers assist in dimer formation. Both interfacial and catalytic site residues control the signal flow crucial for dimerization and enzyme modulation.