Local Unfolding and Aggregation Mechanisms of SOD1: A Monte Carlo Exploration

Copper, zinc superoxide dismutase 1 (SOD1) is a ubiquitous homodimeric enzyme, whose misfolding and aggregation play a potentially key role in the neuro-degenerative disease amyotrophic lateral sclerosis (ALS). SOD1 aggregation is thought to be preceded by dimer dissociation and metal loss, but the mechanisms by which the metal-free monomer aggregates remain incompletely understood. Here we use implicit solvent all-atom Monte Carlo (MC) methods to investigate the local unfolding dynamics of the beta-barrel-forming SOD1 monomer. Although event-to-event variations are large, on average, we find clear differences in dynamics among the eight strands forming the beta-barrel. Most dynamic is the eighth strand, beta 8, which is located in the dimer interface of native SOD1. For the four strands in or near the dimer interface (beta 1, beta 2, beta 7, and beta 8), we perform aggregation simulations to assess the propensity of these chain segments to self-associate. We find that beta 1 and beta 2 readily self-associate to form intermolecular parallel beta-sheets, whereas beta 8 shows a very low aggregation propensity.