Prediction of Misfolding-Specific Epitopes in SOD1 Using Collective Coordinates

We introduce a global, collective coordinate bias into molecular dynamics simulations that partially unfolds a protein, in order to predict misfolding-specific epitopes based on the regions that locally unfold. Several metrics are used to measure local disorder, including solvent exposed surface area (SASA), native contacts (Q), and root mean squared fluctuations (RMSF). The method is applied to Cu, Zn superoxide dismutase (SOD1). For this protein, the processes of monomerization, metal loss, and conformational unfolding due to microenvironmental stresses are all separately taken into account. Several misfolding-specific epitopes are predicted, and consensus epitopes are calculated. These predicted epitopes are consistent with the lower-resolution peptide sequences used to raise disease-specific antibodies, but the epitopes derived from collective coordinates contain shorter, more refined sequences for the key residues constituting the epitope.