Characterization of Familial Amyotrophic Lateral Sclerosis Associated Mutants of the Human CopperZinc Superoxide Dismutase Monomer by Molecular Dynamics Simulations

The inherited form of the progressive motor neuron degenerative disease amyotrophic lateral sclerosis has been linked to over 100 different point mutations in CuZn superoxide dismutase. While the mechanism of disease is not yet understood, there is much evidence that the mutant protein misfolds. This misfolding of the mutant protein could then allow the protein to improperly associate with other misfolded monomer subunits, and it is this soluble oligomer is believed to the toxic species. We used molecular dynamics simulations to explore the structural differences between the mutant and wildtype proteins to gain an understanding of how so many structurally diverse mutations can cause a single phenotype. Our results indicate that the mutant protein is less stable than its wildtype counterpart by a variety of measures. We identify several characteristic changes in the structure and dynamics of many of the implicated mutants that may provide insight into the effects of the mutation on the protein.