Changes in hydrophobicity mainly promotes the aggregation tendency of ALS associated SOD1 mutants

Protein misfolding and aggregation due to mutations, are associated with fatal neurodegenerative disorders. The mutations in Cu/Zn superoxide dismutase (SOD1) causing its misfolding and aggregation are found linked to the motor neuron disorder, amyotrophic lateral sclerosis. Since the mutations are scattered throughout SOD1 structure, determining the exact molecular mechanism underlying the ALS pathology remains unresolved. In this study, we have investigated the major molecular factors that mainly contribute to SOD1 destabilization, intrinsic disorder, and misfolding using sequence and structural information. We have analysed 153 ALS causing SOD1 point mutants for aggregation tendency using four different aggregation prediction tools, viz., Aggrescan3D (A3D), CamSol, GAP and Zyggregator. Our results suggest that 74-79 mutants are susceptible to aggregation, due to distorted native interactions originated at the mutation site. Majority of the aggregation prone mutants are located in the buried regions of SOD1 molecule. Further, the mutations at the hydrophobic amino acids primarily promote the aggregation tendency of SOD1 protein through different destabilizing mechanisms including changes in hydrophobic free energy, loss of electrostatic interactions in the protein's surface and loss of hydrogen bonds that bridges the protein core and surface.