Computational simulation analysis on human SOD1 mutant (H80R) exposes the structural destabilization and the deviation of Zn binding that directs familial amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a devastating progressive disease characterized by motor neuron degeneration causing muscle weakness and paralysis, which ultimately lead to death. The cure for the disease still remains obscure. Further, the available treatments are also not considerably effective on the disease. Subsets of familial ALS (FALS) that is hereditary, accounts for approximately 10% of the cases, while the remaining is sporadic. Mutations in gene encoding superoxide dismutase (SOD1) are the main cause for 20% of FALS cases (Keerthana & Kolandaivel, 2015). SOD1 is a ubiquitous enzyme, which protects the cells from oxidative stress, by catalyzing the superoxide radicals in generating dioxygen and hydrogen peroxide. SOD1 protein constitutes eight antiparallel β-strands and a short helix that supports the electrostatic (residues 121–142) and Zn-binding loops (residues 49–83). SOD1 comprises copper (Cu) and zinc (Zn) cofactors in each subunit, where the Cu and Zn ions are responsible for the dismutation and the stability of SOD1. Particularly, Cu ion binds with His (46, 48, 63 and 120) residues, while Zn ion binds with His (63, 71, 80) and Asp83 residues in Zn loop region. In addition, the disulfide bond (Cys57–Cys146) aids SOD1 to be structurally stable (Kumar, Randhawa, Acharya, Singh, & Kumar, 2016). Till date, more than 150 prominent disease-causing mutations are identified over the entire length of SOD1. The common impacts of mutations in SOD1 include a change in the enzymatic activity and aggregation formation, which cause the increase in toxic function, ultimately leading to motor neuron disease (Chattopadhyay & Valentine, 2009). Based on their location, mutations in SOD1 are characterized into the metal binding and β-barrel mutants. Mutations in the metal binding position cause structural destabilization and weaken the metal coordination. Similarly, the β-barrel mutants affect the stability of SOD1 and diminish their dimer interface. This study aims at unraveling the effect of one such metal binding mutant (H80R) that has been clinically proven through a familial study to be a pathogenic mutant in the ALS case. The substitution in mutant averted the electrostatic loop, which protects the Zn-binding site from the solvent and therefore, the displacement of Zn-binding ligands from their original positions (Seetharaman et al., 2010). In addition, the loss of the Zn ion not only leads to the structural instability and misfolding of SOD1 protein but also makes the protein catalytic inactive even in the presence of the Cu ion. Thus, from the literature, it is to be noted that Zn ion plays a vital role in the structural stability and catalytic activity of the SOD (Kumar et al., 2016). The present study deals with the mutant to provide a molecular insight toward its exploitation over SOD1. Molecular dynamic approaches have been extensively used in various computational studies in order to decipher the effect of the mutation on numerous proteins (Kalsi, Gopalakrishnan, Rajendran, & Purohit, 2016; Keerthana & Kolandaivel, 2015; Purohit, 2014). Thus, in our study we utilized discrete molecular dynamics (DMD) approach to provide a precise understanding over the mutational effect on SOD1 protein. Consequently, the structural changes and the alteration in distance between the Zn and its binding residues, which cause the loss of Zn binding was studied in detail to deliver the foresight on the impact of the mutation on SOD1.