Design of target specific peptide inhibitors using generative deep learning and molecular dynamics simulations.

Journal: Nature communications
PMID: 38383543

Abstract

We introduce a computational approach for the design of target-specific peptides. Our method integrates a Gated Recurrent Unit-based Variational Autoencoder with Rosetta FlexPepDock for peptide sequence generation and binding affinity assessment. Subsequently, molecular dynamics simulations are employed to narrow down the selection of peptides for experimental assays. We apply this computational strategy to design peptide inhibitors that specifically target β-catenin and NF-κB essential modulator. Among the twelve β-catenin inhibitors, six exhibit improved binding affinity compared to the parent peptide. Notably, the best C-terminal peptide binds β-catenin with an IC of 0.010 ± 0.06 μM, which is 15-fold better than the parent peptide. For NF-κB essential modulator, two of the four tested peptides display substantially enhanced binding compared to the parent peptide. Collectively, this study underscores the successful integration of deep learning and structure-based modeling and simulation for target specific peptide design.

Authors

  • Sijie Chen
    Hunan Normal University, College of Engineering and Design, Changsha, Hunan 410000, China.
  • Tong Lin
    The Key Laboratory of Machine Perception (Ministry of Education), School of EECS, Peking University, Beijing, China.
  • Ruchira Basu
    Department of Chemistry and Biochemistry, The Ohio State University, 281 W Lane Ave, Columbus, OH, USA.
  • Jeremy Ritchey
    Department of Chemistry and Biochemistry, The Ohio State University, 281 W Lane Ave, Columbus, OH, USA.
  • Shen Wang
    Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
  • Yichuan Luo
    Electrical and Computer Engineering Department, Carnegie Mellon University, 5000 Forbes Ave, Pittsburgh, PA, USA.
  • Xingcan Li
    Department of Radiology, Affiliated Hospital and Medical School of Nantong University, 20 West Temple Road, Nantong, Jiangsu, China.
  • Dehua Pei
    Department of Chemistry and Biochemistry, The Ohio State University, 281 W Lane Ave, Columbus, OH, USA. pei.3@osu.edu.
  • Levent Burak Kara
    Mechanical Engineering Department, Carnegie Mellon University, 5000 Forbes Ave, Pittsburgh, PA, USA. lkara@cmu.edu.
  • Xiaolin Cheng
    Laboratory of Laparoscopic Technique and Engineering, Qilu Hospital of Shandong University, Jinan, Shandong, People's Republic of China.

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