WSME model

We employ the Ising-like WSME model (Wako and Saitô, 1978; Muñoz and Eaton, 1999) with the block approximation (Gopi et al., 2019) to predict the conformational landscape of SOD1 oxidized monomer and its variants using the PDB structure 4FF9 as the reference. Briefly, the model assigns binary variables of 1 or 0 for folded or unfolded status of residues, respectively. We employ a version of the model that accounts of single-stretches of folded blocks (single-sequence approximation), two stretches of folded blocks (double-sequence approximation [DSA]) and DSA allowing for interactions across the folded islands if they are interacting in the folded structure. The 151-residue protein SOD1 is therefore reduced to a collection of 49 sequential blocks on assuming a block length of 3 thus reducing the number of microstates from >42,700,000 (in the residue-level version of the model) to 461,826. The energetics of the model involves van der Waals interactions identified with a 6 Å heavy-atom cut-off, all-to-all Debye–Hückel electrostatics, and simplified solvation (defined by the heat capacity change per native contact of) (Naganathan, 2012). Residues identified to be fully folded are assigned an entropic penalty of −13.6 J mol⁻¹ K⁻¹ per residue (ΔS_conf). The apo form of SOD1 is simulated by assigning an excess conformational entropy of −19.7 J mol⁻¹ K⁻¹ per residue (Rajasekaran et al., 2016) for the stretches of residues 49–82 (loop IV, Zn binding loop) and 121–142 (loop VII, Cu binding loop), as reported from NMR order parameter measurements (Sekhar et al., 2015). To simulate order in either one or both the loops, the conformational entropy of residues in the loop is modified to −13.6 J mol⁻¹ K⁻¹ per residue (i.e. a lower penalty for folding), thus mimicking the variants of SOD1 (Zn bound, Cu bound, and Holo forms). The van der Waals interaction energies are fixed to −35.9, –38.2, −42.2, and −48.9 J mol⁻¹ for the Holo, Zn bound, Cu bound, and apo variants, respectively, to simulate iso-stability conditions at 298 K. The heat capacity change per native contact is fixed to −0.36 J mol⁻¹ K⁻¹ per native contact. All prolines are assigned an entropic penalty of zero to account for their rigidity. Residue probabilities and folding mechanism as a function of the number of structured blocks are predicted at iso-stability conditions (i.e. a stability 25 kJ mol⁻¹ at 298 K) following established protocols by accumulating partial partition functions.