NCPepFold: Accurate Prediction of Noncanonical Cyclic Peptide Structures via Cyclization Optimization with Multigranular Representation.

Artificial intelligence-based peptide structure prediction methods have revolutionized biomolecular science. However, restricting predictions to peptides composed solely of 20 natural amino acids significantly limits their practical application; as such, peptides often demonstrate poor stability under physiological conditions. Here, we present NCPepFold, a computational approach that can utilize a specific cyclic position matrix to directly predict the structure of cyclic peptides with noncanonical amino acids. By integrating multigranularity information at the residual and atomic level, along with fine-tuning techniques, NCPepFold significantly improves prediction accuracy, with the average peptide root-mean-square deviation (RMSD) for cyclic peptides being 1.640 Å. In summary, this is a novel deep learning model designed specifically for cyclic peptides with noncanonical amino acids, offering great potential for peptide drug design and advancing biomedical research.