CATHe: detection of remote homologues for CATH superfamilies using embeddings from protein language models

Motivation: CATH is a protein domain classification resource that exploits an automated workflow of structure and sequence comparison alongside expert manual curation to construct a hierarchical classification of evolutionary and structural relationships. The aim of this study was to develop algorithms for detecting remote homologues missed by state-of-the-art hidden Markov model (HMM)-based approaches. The method developed (CATHe) combines a neural network with sequence representations obtained from protein language models. It was assessed using a dataset of remote homologues having less than 20% sequence identity to any domain in the training set. Results: The CATHe models trained on 1773 largest and 50 largest CATH superfamilies had an accuracy of 85.6 6 0.4% and 98.2 6 0.3%, respectively. As a further test of the power of CATHe to detect more remote homologues missed by HMMs derived from CATH domains, we used a dataset consisting of protein domains that had annotations in Pfam, but not in CATH. By using highly reliable CATHe predictions (expected error rate <0.5%), we were able to provide CATH annotations for 4.62 million Pfam domains. For a subset of these domains from Homo sapiens, we structurally validated 90.86% of the predictions by comparing their corresponding AlphaFold2 structures with structures from the CATH superfamilies to which they were assigned.