title: An in silico study of the effect of SOD1 electrostatic loop dynamics on amyloid‑like filament formation.
abstract: Superoxide dismutase [Cu-Zn], or SOD1, is a homo-dimeric protein that functions as an antioxidant by scavenging for superoxides. A wide range of SOD1 variants are linked to inherited, or familial, amyotrophic lateral sclerosis, a progressive and fatal neurodegenerative disease. Aberrant SOD1 oligomerization has been strongly implicated in disease causation, even for sporadic ALS, or SALS, which accounts for ~90 % of ALS cases. Small heat shock proteins (sHSP) have been shown to protect against amyloid fibril formation in vitro, and the sHSP αB-crystallin suppresses in vitro aggregation of SOD1. We are seeking to elucidate the structural features of both SOD1 amyloid formation and αB-crystallin amyloid suppression. Specifically, we have used a flexible docking protocol to refine our model of a SOD1 non-obligate tetramer, postulated to function as a transient desolvating complex. Homology modeling and molecular dynamics (MD) are used to supply the missing structural elements of a previously characterized SOD1 amyloid filament, thereby providing a structural analysis for the observed gain of interaction. This completed filament is then further modified using MD to provide a structural model for protofibril capping of SOD1 filaments by αB-crystallin.
authors: Department of Chemistry, St. Edward's University, Austin, TX, 78704, USA. healy@stedwards.edu.
authors: Eamonn F
authors: EF
authors: Healy
authors: Department of Chemistry, St. Edward's University, Austin, TX, 78704, USA.
authors: Luis
authors: L
authors: Cervantes
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry*; D003198:Computer Simulation; D006801:Humans; D006860:Hydrogen Bonding; D056004:Molecular Dynamics Simulation; D009154:Mutation; D066329:Protein Aggregates; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D055672:Static Electricity; D000072105:Superoxide Dismutase-1 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D038201:alpha-Crystallins / Q000737:chemistry / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D066329:Protein Aggregates; D038201:alpha-Crystallins; D000072105:Superoxide Dismutase-1
keywords: Amyotrophic lateral sclerosis; Electrostatic loop; Superoxide dismutase; αB-crystallin