Abstract
In this work, we investigate the β-barrel of superoxide dismutase 1 (SOD1) in a mutated form, the isoleucine 35 to alanine (I35A) mutant, commonly used as a model system to decipher the role of the full-length apoSOD1 protein in amyotrophic lateral sclerosis (ALS). It is known from experiments that the mutation reduces the stability of the SOD1 barrel and makes it largely unfolded in the cell at 37 degrees Celsius. We deploy state-of-the-art computational machinery to examine the thermal destabilization of the I35A mutant by comparing two widely used force fields, Amber a99SB-disp and CHARMM36m. We find that only the latter force field, when combined with the Replica Exchange with Solute Scaling (REST2) approach, reproduces semi-quantitatively the experimentally observed shift in the melting between the original and the mutated SOD1 barrel. In addition, we analyze the unfolding process and the conformational landscape of the mutant, finding these largely similar to those of the wildtype. Nevertheless, we detect an increased presence of partially misfolded states at ambient temperatures. These states, featuring conformational changes in the region of the β-strands β4-β6, might provide a pathway for nonnative aggregation.