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Superoxide dismutase (SOD) is the primary enzyme of the cellular antioxidant defense cascade. Misfolding, concomitant oligomerization, and higher order aggregation of human cytosolic SOD are linked to amyotrophic lateral sclerosis (ALS). Although, with two metal ion cofactors SOD1 is extremely robust, the de-metallated apo form is intrinsically disordered. Since the rise of oxygen-based metabolism and antioxidant defense systems are evolutionary coupled, SOD is an interesting protein with a deep evolutionary history. We deployed statistical analysis of sequence space to decode evolutionarily co-varying residues in this protein. These were validated by applying graph theoretical modelling to understand the impact of the presence of metal ion co-factors in dictating the disordered (apo) to hidden disordered (wild-type SOD1) transition. Contact maps were generated for different variants, and the selected significant residues were mapped on separate structure networks. Sequence space analysis coupled with structure networks helped us to map the evolutionarily coupled co-varying patches in the SOD1 and its metal-depleted variants. In addition, using structure network analysis, the residues with a major impact on the internal dynamics of the protein structure were investigated. Our results reveal that the bulk of these evolutionarily co-varying residues are localized in the loop regions and positioned differentially depending upon the metal residence and concomitant steric restrictions of the loops.

Evolutionary Analyses of Sequence and Structure Space Unravel the Structural Facets of SOD1