HaloClass: Salt-Tolerant Protein Classification with Protein Language Models

Salt-tolerant proteins, also known as halophilic proteins, have unique adaptations to function in high-salinity environments. These proteins have naturally evolved in extremophilic organisms, and more recently, are being increasingly applied as enzymes in industrial processes. Due to an abundance of salt-tolerant sequences and a simultaneous lack of experimental structures, most computational methods to predict stability are sequence-based only. These approaches, however, are hindered by a lack of structural understanding of these proteins. Here, we present HaloClass, an SVM classifier that leverages ESM-2 protein language model embeddings to accurately identify salt-tolerant proteins. On a newer and larger test dataset, HaloClass outperforms existing approaches when predicting the stability of never-before-seen proteins that are distal to its training set. Finally, on a mutation study that evaluated changes in salt tolerance based on single- and multiple-point mutants, HaloClass outperforms existing approaches, suggesting applications in the guided design of salt-tolerant enzymes.