HelixGAN a deep-learning methodology for conditional de novo design of α-helix structures

MOTIVATION: Protein and peptide engineering has become an essential field in biomedicine with therapeutics, diagnostics and synthetic biology applications. Helices are both abundant structural feature in proteins and comprise a major portion of bioactive peptides. Precise design of helices for binding or biological activity is still a challenging problem. RESULTS: Here, we present HelixGAN, the first generative adversarial network method to generate de novo left-handed and right-handed alpha-helix structures from scratch at an atomic level. We developed a gradient-based search approach in latent space to optimize the generation of novel α-helical structures by matching the exact conformations of selected hotspot residues. The designed α-helical structures can bind specific targets or activate cellular receptors. There is a significant agreement between the helix structures generated with HelixGAN and PEP-FOLD, a well-known de novo approach for predicting peptide structures from amino acid sequences. HelixGAN outperformed RosettaDesign, and our previously developed structural similarity method to generate D-peptides matching a set of given hotspots in a known L-peptide. As proof of concept, we designed a novel D-GLP1₁ analog that matches the conformations of critical hotspots for the GLP1 function. MD simulations revealed a stable binding mode of the D-GLP1₁ analog coupled to the GLP1 receptor. This novel D-peptide analog is more stable than our previous D-GLP1 design along the MD simulations. We envision HelixGAN as a critical tool for designing novel bioactive peptides with specific properties in the early stages of drug discovery. AVAILABILITY AND IMPLEMENTATION: https: //github. com/xxiexuezhi/helixgan. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.