Abstract Details Title A Computational Model of the Mutations of Cu-Zn Superoxide Dismutase 1 and Mechanisms for Protein Misfolding in Amyotrophic Lateral Sclerosis with Theoretical Nuclear Physics Methods Topic General Neurology Presentation(s) S13 - Advances in General Neurology (2:08 PM-2:16 PM) Poster/Presentation Number 002 Objective To elaborate a computational model of the mutations of Cu-Zn superoxide dismutase 1 and mechanisms for protein misfolding in amyotrophic lateral sclerosis with theoretical nuclear physics methods. Background Superoxide dismutase 1 (SOD1), profilin 1 (PFN1) protein, FUS protein and C9orf72 protein play a key role in amyotrophic lateral sclerosis (ALS) pathogenesis. It is thought that misfolded mutant SOD1 can cause misfolding and aggregation of wild-type SOD1 in neighboring neurons in a prion-like manner. Design/Methods Computational design at the Density Functional Theory level, docking studies, computed IR-active modes, HOMO-LUMO gaps, UV-vis absorbance spectroscopy, periodic density functional theory (DFT) framework, Kohn–Sham equations, Powel algorithm method and molecular dynamics methods were applied in the computational analysis. PhD-SNP, PMUT, PolyPhen-2, SIFT, SNAP, SNPS&GO, SAAP, nsSNPAnalyzer, SNPeffect4.0 and I-Mutant2.0 were used to predict the functional and stability effects of SOD1, FUS, C9orf72 and PFN1 mutations. The molecular docking was conducted with the tool AutoDock Vina (version 1.1.2), as implemented in the MolAr (Molecular Architecture) software. ConSurf was used for the evolutionary conservation analysis. The key docking complexes were evaluated by molecular dynamics (MD) simulation using the GROMOSA7 all-atom force field and performed using GROMACS 5.1 software. Results The computational model of this work suggests that the location of the FUS protein is slightly greater in the cytoplasm of cells carrying the R521H mutation in the FUS gene. Computational analysis suggests that the studied mutations could affect the PFN1 flexibility at the actin and PLP-binding domains, and consequently, their intermolecular interactions. Alterations in the functions of the SOD1 protein due to allosteric regulatory disorders can induce the aggregation of the mutated SOD1. Conclusions Understanding the mutations of Cu-Zn superoxide dismutase 1 and mechanisms for protein misfolding in ALS promises to not only promote effective design of ALS therapeutics, but also provides a broader understanding of pathophysiological mechanisms of neurodegenerative diseases. Authors/Disclosures João Marcos Brandet PRESENTER Mr. Brandet has nothing to disclose.