Molecular dynamics (MD) simulation study on holo and apo forms of the ALS-linked hSOD۱ mutation

Familial amyotrophic lateral sclerosis (fALS) is a neurodegenerative disorder; approximately ۲۰% is caused by dominant mutations in the gene encoding Cu/Zn human superoxide dismutase (hSOD۱). Several mutations have been identified and linked to ALS. This study was designed to evaluate the e↵ect of ALS-associated point mutation, namely N۶۵S, located in loop IV, on structure properties. Molecular dynamics (MD) simulation was performed in order to investigate the possible e↵ects of mutation on the structure of the wild-type protein and compare it with the mutant protein. According to the dynamic analysis, the effect of N۶۵S mutation on the stability of SOD۱ protein was predicted and significant structural differences between wild-type and N۶۵S mutant were observed in terms of the radius of gyration (Rg). The average values of Rg were (۱/۴۴±۰.۰۱۰), (۱/۴۴±۰.۰۱۱), (۱/۴۴±۰.۰۱۷), and (۱/۴۱±۰.۰۱۳) ˚Afor apo and holo of wild-type and N۶۵S mutant, respectively. Also, to check the second structure, which, based on the hydrogen bond patterns and some geometrical constraints, each residue is assigned to one of the possible states (↵α- helices,β -sheet). The secondary structure parameters of hSOD۱ exhibited significant changes upon N۶۵S mutation. There is no change of β Sheet content in the form apo wild-type and mutant, while contents of -β Sheet in the form holo Wild-type were more than that of form holo mutant. There is no change of ↵α-helices content in the form holo wild-type and mutant, while contents of ↵α helices in the form apo wild-type were more than that of the form apo mutant. The results of this study showed that the occurrence of mutation at the loop IV of the SOD۱ mutant causes conformational changes which lead to neurodegeneration disorders in humans. These findings provided insight into the e↵ect of mutations on the hSOD۱, which leads to neurodegeneration disorders in humans.