Computational insight into in silico analysis and molecular dynamics simulation of the dimer interface residues of ALS-linked hSOD1 forms in apo/holo states: a combined experimental and bioinformatic perspective

Hamza Dakhil Zaji; Bagher Seyedalipour; Haider Munzer Hanun; Payam Baziyar; Saman Hosseinkhani; Mona Akhlaghi

doi:10.1007/s13205-023-03514-1

Computational insight into in silico analysis and molecular dynamics simulation of the dimer interface residues of ALS-linked hSOD1 forms in apo/holo states: a combined experimental and bioinformatic perspective

3 Biotech. 2023 Mar;13(3):92. doi: 10.1007/s13205-023-03514-1. Epub 2023 Feb 21.

Authors

Hamza Dakhil Zaji¹, Bagher Seyedalipour¹, Haider Munzer Hanun¹, Payam Baziyar¹, Saman Hosseinkhani², Mona Akhlaghi¹

Affiliations

¹ Department of Molecular and Cell Biology, Faculty of Basic Science, University of Mazandaran, Babolsar, Iran.
² Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran.

Abstract

The aggregation of misfolded SOD1 proteins in neurodegenerative illnesses is a key pathological hallmark in amyotrophic lateral sclerosis (ALS). SOD1 is stabilized and enzymatically activated after binding to Cu/Zn and forming intramolecular disulfide. SOD1 aggregation/oligomerization is triggered by the dissociation of Cu and/or Zn ions. Therefore, we compared the possible effects of ALS-associated point mutations of the holo/apo forms of WT/I149T/V148G SOD1 variants located at the dimer interface to determine structural characterization using spectroscopic methods, computational approaches as well as molecular dynamics (MD) simulations. Predictive results of computational analysis of single-nucleotide polymorphisms (SNPs) suggested that mutant SOD1 has a deleterious effect on activity and structure destabilization. MD data analysis indicated that changes in flexibility, stability, hydrophobicity of the protein as well as increased intramolecular interactions of apo-SOD1 were more than holo-SOD1. Furthermore, a decrease in enzymatic activity in apo-SOD1 was observed compared to holo-SOD1. Comparative intrinsic and ANS fluorescence results of holo/apo-WT-hSOD1 and mutants indicated structural alterations in the local environment of tryptophan residue and hydrophobic patches, respectively. Experimental and MD data supported that substitution effect and metal deficiency of mutants (apo forms) in the dimer interface may promote the tendency to protein mis-folding and aggregation, consequently disrupting the dimer-monomer equilibrium and increased propensity to dissociation dimer into SOD-monomer ultimately leading to loss of stability and function. Overall, data analysis of apo/holo SOD1 forms on protein structure and function using computational and experimental studies will contribute to a better understanding of ALS pathogenicity.

Keywords: Amyotrophic lateral sclerosis; Dimer interface; Human superoxide dismutase 1; Molecular dynamics simulations; Protein aggregation; Structural stability.

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