How informative are structural alphabets for representing protein folds?

Abstract Amino acid sequences are the primary basis for protein comparison, but sequenc similarity is often difficult to detect between distantly related proteins, even whe folds remain conserved. Therefore, comparing three-dimensional (3D) protein stru can reveal relationships that are not apparent from sequence alone. Full structur alignment uses 3D coordinates, whereas structural alphabets represent protein structures as sequences of discrete states. These alphabets differ in granularity: represents helices, strands, and loops using three states; Q8 uses the eight secondary-structure states defined by DSSP; and the 20-state 3Di alphabet, dev for Foldseek, describes tertiary residue-residue interactions. Here, we quantified fold-level information retained by Q3, Q8, and 3Di across three CATH and SCO fold-recognition benchmarks, using TM-scores as the reference measure of full-str similarity. The results reveal a Pareto-like trade-off: despite reducing protein str to a linear pattern of helices, strands, and loops and discarding explicit informat about spatial distances, residue orientations, and tertiary contacts, Q3 preserves approximately 90-96% of the global fold-recognition signal available from full-st comparison and is on par with the richer 20-state 3Di alphabet. Although Q3 lac fine-grained structural details needed to capture the remaining signal, it provide simple, interpretable, and information-rich representation of protein-fold similarit central purpose of this study is therefore to quantify the fold-level information re by a three-state secondary-structure representation, rather than to introduce Q3 alternative to full structural comparison or optimized search methods.