StaPep: An Open-Source Toolkit for Structure Prediction, Feature Extraction, and Rational Design of Hydrocarbon-Stapled Peptides

J Chem Inf Model. 2024 Dec 23;64(24):9361-9373. doi: 10.1021/acs.jcim.4c01718. Epub 2024 Nov 6.

Abstract

All-hydrocarbon stapled peptides, with their covalent side-chain constraints, provide enhanced proteolytic stability and membrane permeability, making them superior to linear peptides. However, tools for extracting structural and physicochemical descriptors to predict the properties of hydrocarbon-stapled peptides are lacking. To address this, we present StaPep, a Python-based toolkit for generating 3D structures and calculating 21 features for hydrocarbon-stapled peptides. StaPep supports peptides containing two non-standard amino acids (norleucine and 2-aminoisobutyric acid) and six non-natural anchoring residues (S3, S5, S8, R3, R5, and R8), with customization options for other non-standard amino acids. We showcase StaPep's utility through three case studies. The first generates 3D structures of these peptides with a mean RMSD of 1.62 ± 0.86, offering essential structural insights for drug design and biological activity prediction. The second develops machine learning models based on calculated molecular features to differentiate between membrane-permeable and non-permeable stapled peptides, achieving an AUC of 0.93. The third constructs regression models to predict the antimicrobial activity of stapled peptides against Escherichia coli, with a Pearson correlation of 0.84. StaPep's pipeline spans data retrieval, structure generation, feature calculation, and machine learning modeling for hydrocarbon-stapled peptides. The source codes and data set are freely available on Github: https://github.com/dahuilangda/stapep_package.

MeSH terms

  • Drug Design*
  • Hydrocarbons* / chemistry
  • Machine Learning
  • Models, Molecular
  • Peptides* / chemistry
  • Protein Conformation
  • Software*

Substances

  • Hydrocarbons
  • Peptides