Predicting Antimicrobial Peptides Using ESMFold-Predicted Structures and ESM-2-Based Amino Acid Features with Graph Deep Learning

Currently, antimicrobial resistance constitutes a serious threat to human health. Drugs based on antimicrobial peptides (AMPs) constitute one of the alternatives to address it. Shallow and deep learning (DL)-based models have mainly been built from amino acid sequences to predict AMPs. Recent advances in tertiary (3D) structure prediction have opened new opportunities in this field. In this sense, models based on graphs derived from predicted peptide structures have recently been proposed. However, these models are not in correspondence with state-of-the-art approaches to codify evolutionary information, and, in addition, they are memory- and time-consuming because depend on multiple sequence alignment. Herein, we presented a framework to create alignment-free models based on graph representations generated from ESMFold-predicted peptide structures, whose nodes are characterized with amino acid-level evolutionary information derived from the Evolutionary Scale Modeling (ESM-2) models. A graph attention network (GAT) was implemented to assess the usefulness of the framework in the AMP classification. To this end, a set comprised of 67,058 peptides was used. It was demonstrated that the proposed methodology allowed to build GAT models with generalization abilities consistently better than 20 state-of-the-art non-DL-based and DL-based models. The best GAT models were developed using evolutionary information derived from the 36- and 33-layer ESM-2 models. Similarity studies showed that the best-built GAT models codified different chemical spaces, and thus they were fused to significantly improve the classification. In general, the results suggest that esm-AxP-GDL is a promissory tool to develop good, structure-dependent, and alignment-free models that can be successfully applied in the screening of large data sets. This framework should not only be useful to classify AMPs but also for modeling other peptide and protein activities.