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Integrative residue-intuitive machine learning and MD Approach to Unveil Allosteric Site and Mechanism for β2AR

Author

Listed:
  • Xin Chen

    (Sichuan University)

  • Kexin Wang

    (Sichuan University)

  • Jianfang Chen

    (Sichuan University)

  • Chao Wu

    (Sichuan University)

  • Jun Mao

    (Sichuan University)

  • Yuanpeng Song

    (Sichuan University)

  • Yijing Liu

    (Sichuan University)

  • Zhenhua Shao

    (Sichuan University
    Tianfu Jincheng Laboratory)

  • Xuemei Pu

    (Sichuan University)

Abstract

Allosteric drugs offer a new avenue for modern drug design. However, the identification of cryptic allosteric sites presents a formidable challenge. Following the allostery nature of residue-driven conformation transition, we propose a state-of-the-art computational pipeline by developing a residue-intuitive hybrid machine learning (RHML) model coupled with molecular dynamics (MD) simulation, through which we can efficiently identify the allosteric site and allosteric modulator as well as reveal their regulation mechanism. For the clinical target β2-adrenoceptor (β2AR), we discover an additional allosteric site located around residues D792.50, F2826.44, N3187.45 and S3197.46 and one putative allosteric modulator ZINC5042. Using Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) and protein structure network (PSN), the allosteric potency and regulation mechanism are probed to further improve identification accuracy. Benefiting from sufficient computational evidence, the experimental assays then validate our predicted allosteric site, negative allosteric potency and regulation pathway, showcasing the effectiveness of the identification pipeline in practice. We expect that it will be applicable to other target proteins.

Suggested Citation

  • Xin Chen & Kexin Wang & Jianfang Chen & Chao Wu & Jun Mao & Yuanpeng Song & Yijing Liu & Zhenhua Shao & Xuemei Pu, 2024. "Integrative residue-intuitive machine learning and MD Approach to Unveil Allosteric Site and Mechanism for β2AR," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52399-y
    DOI: 10.1038/s41467-024-52399-y
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    References listed on IDEAS

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