A high‐throughput predictive method for sequence‐similar fold switchers

Although most experimentally characterized proteins with similar sequences assume the same folds and perform similar functions, an increasing number of exceptions is emerging. One class of exceptions comprises sequence‐similar fold switchers, whose secondary structures shift from α‐helix β‐sheet through a small number of mutations, a sequence insertion, or a deletion. Predictive methods for identifying sequence‐similar fold switchers are desirable because some are associated with disease and/or can perform different functions in cells. Here, we use homology‐based secondary structure predictions to identify sequence‐similar fold switchers from their amino acid sequences alone. To do this, we predicted the secondary structures of sequence‐similar fold switchers using three different homology‐based secondary structure predictors: PSIPRED, JPred4, and SPIDER3. We found that α‐helix β‐strand prediction discrepancies from JPred4 discriminated between the different conformations of sequence‐similar fold switchers with high statistical significance (P