Molecular dynamics analysis of superoxide dismutase 1 mutations suggests decoupling between mechanisms underlying ALS onset and progression

• Published in: Computational and structural biotechnology journal 2023-01, Vol.21, p.5296-5308
• Main Authors: Kalia, Munishikha, Miotto, Mattia, Ness, Deborah, Opie-Martin, Sarah, Spargo, Thomas P., Di Rienzo, Lorenzo, Biagini, Tommaso, Petrizzelli, Francesco, Al Khleifat, Ahmad, Kabiljo, Renata, Mazza, Tommaso, Ruocco, Giancarlo, Milanetti, Edoardo, Dobson, Richard JB, Al-Chalabi, Ammar, Iacoangeli, Alfredo
• Format: Article
• Language: English
• Subjects: Amyotrophic lateral sclerosis; Diseaseassociated SOD1 mutations; Molecular dynamics (MD) simulations; Performed principal component analysis; Superoxide Dismutase type 1 (SOD1); Survival analysis
• ISSN: 2001-0370; 2001-0370
• DOI: 10.1016/j.csbj.2023.09.016

Mutations in the superoxide dismutase 1 (SOD1) gene are the second most common known cause of ALS. SOD1 variants express high phenotypic variability and over 200 have been reported in people with ALS. It was previously proposed that variants can be broadly classified in two groups, ‘wild-type like’ (WTL) and ‘metal binding region’ (MBR) variants, based on their structural location and biophysical properties. MBR variants, but not WTL variants, were associated with a reduction of SOD1 enzymatic activity. In this study we used molecular dynamics and large clinical datasets to characterise the differences in the structural and dynamic behaviour of WTL and MBR variants with respect to the wild-type SOD1, and how such differences influence the ALS clinical phenotype. Our study identified marked structural differences, some of which are observed in both variant groups, while others are group specific. Moreover, collecting clinical data of approximately 500 SOD1 ALS patients carrying variants, we showed that the survival time of patients carrying an MBR variant is generally longer (∼6 years median difference, p