Target specific peptide design using latent space approximate trajectory collector

Abstract Despite the prevalence and many successes of deep learning applications in de novo molecular design, the problem of peptide generation targeting specific proteins remains unsolved. A main barrier for this is the scarcity of the high-quality training data. To tackle the issue, we propose a novel machine learning based peptide design architecture, called Latent Space Approximate Trajectory Collector (LSATC). It consists of a series of samplers on an optimization trajectory on a highly non-convex energy landscape that approximates the distributions of peptides with desired properties in a latent space. The process involves little human intervention and can be implemented in an end-to-end manner. We demonstrate the model by the design of peptide extensions targeting β-catenin, a key nuclear effector protein involved in canonical Wnt signalling. When compared with a random sampler, LSATC can sample peptides with 36% lower mean binding scores in a 16 times smaller interquartile range (IQR) and 284% less mean hydrophobicity with a 1.4 times smaller IQR. LSATC also largely outperforms other common generative models.Finally, we utilize a clustering algorithm to select 4 peptides from the100 LSATC designed peptides for experimental validation. The resultconfirms that all the four peptides extended by LSATC show improved β-catenin binding by at least 20.0%, and two of the peptides show a 3 fold increase in binding affinity as compared to the base peptide.