PepFoundry: A Pipeline for Building Machine-Learning Ready Representations of Nonstandard Peptides Containing Cycles, Non-natural Residues, Polymer Units, and More

Abstract

Peptides featuring synthetic modifications, such as noncanonical amino acids, backbone modifications, cyclic structures, and polymer units have become central to modern drug design due to their enhanced stability and functional diversity. However, current machine learning (ML) approaches are restricted by challenges associated with transforming peptide sequences into atom-level representations, leading ML efforts to focus largely on datasets containing linear peptides comprised of standard residues. Here, we present PepFoundry, a Python package that handles peptide sequences beyond canonical amino acids and linear topologies by using SMILES strings in the CHUCKLES format. PepFoundry generates atom-mapped RDKit molecule objects, enabling the extraction of atom-level features, such as Morgan fingerprints and graph representations. We demonstrate its utility by processing a dataset of peptide sequences containing noncanonical amino acids and generating atomic level features for downstream property prediction. We show that atomic-level representations of peptides containing noncanonical amino acids consistently outperform sequence-level representations, regardless of model type. We additionally explore the representation of noncanonical peptides through latent space visualization and show that models with atomic-level information can effectively learn relationships between analogous sequences of l-peptides, d-peptides, and peptoids. This framework allows for the flexible incorporation of new amino acid chemistries, enabling existing ML methods to be straightforwardly applied to datasets of peptides containing nonstandard features. It also facilitates the rapid construction of customized peptide libraries and provides a scalable platform to accelerate ML-driven peptide discovery and optimization.