Study of mutation and misfolding of Cu-Zn SOD1 protein.

The main objective of this work is to determine the mechanism for misfolding and aggregation as a result of mutations in Cu-Zn superoxide dismutase1. The quantum mechanical approach is beneficial for investigating the early stages of mutation, misfolding, and loss of protection of the native structures involved in the neuro-degeneration disease Amyotrophic Lateral Sclerosis. All the structures were optimized using density functional theory (B3LYP) with 6-31G* and LANL2DZ basis sets. The binding energies of the metal ions with their associated residues in the active site loop and metal binding loop have been investigated for native and metal-bound mutated structures. The metal ion affinity (MIA) was computed for all the structures. The binding energy and MIA in gas phase reveal the nature of interaction of active site residues with the metal cations. The electronic effect prevailing between the side chains of the residues in the active site governing the intermolecular interactions is given by the polarizability studies. The role of the bridging residue His 63 in the active site of the protein in the native and metal-bound mutated structures have been studied using ONIOM method to reveal the changes that takes place in the structural parameters during mutation. The molecular dynamics simulation is used to explore different dynamic properties of active site in native and metal-bound mutated structures. The structural information provided by the molecular dynamics simulation illustrates the structural consequences in the mutated structures.