Cu,Zn superoxide dismutase (SOD1) has been implicated in the familial form of
the neurodegenerative disease Amyotrophic Lateral Sclerosis (ALS). It has been
suggested that mutant mediated SOD1 misfolding/aggregation is an integral part
of the pathology of ALS. We study the folding thermodynamics and kinetics of
SOD1 using a hybrid molecular dynamics approach. We reproduce the
experimentally observed SOD1 folding thermodynamics and find that the residues
which contribute the most to SOD1 thermal stability are also crucial for
apparent two-state folding kinetics. Surprisingly, we find that these residues
are located on the surface of the protein and not in the hydrophobic core.
Mutations in some of the identified residues are found in patients with the
disease. We argue that the identified residues may play an important role in
aggregation. To further characterize the folding of SOD1, we study the role of
cysteine residues in folding and find that non-native disulfide bond formation
may significantly alter SOD1 folding dynamics and aggregation propensity.Comment: 16 pages, 5 figure
