Comprehensive in silico analysis and molecular dynamics of the superoxide dismutase 1 (SOD1) variants related to amyotrophic lateral sclerosis.

Gabriel Rodrigues Coutinho Pereira,Joelma Freire De Mesquita,Bárbara De Azevedo Abrahim Vieira,Maria Gasset

doi:10.1371/journal.pone.0247841

Gabriel Rodrigues Coutinho Pereira, Joelma Freire De Mesquita + Show 2 more

Open Access

https://doi.org/10.1371/journal.pone.0247841

Copy DOI

Abstract

Amyotrophic Lateral Sclerosis (ALS) is the most frequent motor neuron disorder, with a significant social and economic burden. ALS remains incurable, and the only drugs approved for its treatments confers a survival benefit of a few months for the patients. Missense mutations in superoxide dismutase 1 (SOD1), a major cytoplasmic antioxidant enzyme, has been associated with ALS development, accounting for 23% of its familial cases and 7% of all sporadic cases. This work aims to characterize in silico the structural and functional effects of SOD1 protein variants. Missense mutations in SOD1 were compiled from the literature and databases. Twelve algorithms were used to predict the functional and stability effects of these mutations. ConSurf was used to estimate the evolutionary conservation of SOD1 amino-acids. GROMACS was used to perform molecular dynamics (MD) simulations of SOD1 wild-type and variants A4V, D90A, H46R, and I113T, which account for approximately half of all ALS-SOD1 cases in the United States, Europe, Japan, and United Kingdom, respectively. 233 missense mutations in SOD1 protein were compiled from the databases and literature consulted. The predictive analyses pointed to an elevated rate of deleterious and destabilizing predictions for the analyzed variants, indicating their harmful effects. The ConSurf analysis suggested that mutations in SOD1 mainly affect conserved and possibly functionally essential amino acids. The MD analyses pointed to flexibility and essential dynamics alterations at the electrostatic and metal-binding loops of variants A4V, D90A, H46R, and I113T that could lead to aberrant interactions triggering toxic protein aggregation. These alterations may have harmful implications for SOD1 and explain their association with ALS. Understanding the effects of SOD1 mutations on protein structure and function facilitates the design of further experiments and provides relevant information on the molecular mechanism of pathology, which may contribute to improvements in existing treatments for ALS.

Highlights

Amyotrophic Lateral Sclerosis (ALS) is a highly disabling, progressive, and fatal neurodegenerative disorder characterized by injury and death of upper motor neurons in the cerebral cortex and lower motor neurons in the brain stem and spinal cord [1]
The variants A4V, D90A, H46R, and I113T were selected for the molecular dynamics (MD) simulations because they account for approximately half of all ALS-superoxide dismutase 1 (SOD1) cases in the United States [39], Europe, Japan, and United Kingdom [15], respectively
The electrostatic loop is composed of positively charged amino-acids that guide superoxide radicals into the SOD1 active site where the copper ion is located [41]

Summary

Introduction

Amyotrophic Lateral Sclerosis (ALS) is a highly disabling, progressive, and fatal neurodegenerative disorder characterized by injury and death of upper motor neurons in the cerebral cortex and lower motor neurons in the brain stem and spinal cord [1]. ALS is characterized by the progressive loss of voluntary motor activity, which impairs the patient’s ability to work and perform daily activities [2], usually resulting in the patient’s death due to respiratory paralysis within three to four years after the symptoms’ onset [3]. ALS is the most frequent motor neurodegenerative disorder in adults [5], affecting more than 220,000 people worldwide. The number of people affected by ALS is projected to increase by 69% in the 20 years, among developing countries [6]. There is an urgent need to develop more effective treatments for diseases such as ALS, but these will only come with a deep understanding of their causes and associated mechanisms [9]. Glutamate cytotoxicity, inflammatory pathway, oxidative stress, and protein aggregation are among the main mechanisms associated with ALS development [11]

Objectives

Methods

Results

Discussion

Conclusion