4.7 Article

Leveraging Protein Dynamics to Identify Functional Sites Models

Journal

JOURNAL OF CHEMICAL INFORMATION AND MODELING
Volume 62, Issue 14, Pages 3331-3345

Publisher

AMER CHEMICAL SOC
DOI: 10.1021/acs.jcim.2c004843331J

Keywords

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Funding

  1. Key Laboratory of Systems Biomedicine (Ministry of Education)
  2. Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University [KLSB2019KF-02]
  3. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences [SIMM2205KF-11]
  4. National Natural Science Foundation of China [31872723, 61303108]
  5. Natural Science Foundation of Jiangsu Province [BK20211102]
  6. Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions

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This research presents two deep learning models, cDL-PAU and cDL-FuncPhos, that incorporate sequence, structure, and dynamics-based features to predict post-translational modifications (PTMs). The models achieve satisfactory prediction scores and provide insights into the molecular basis and functional landscape of PTMs.
Accurate prediction of post-translational modifications (PTMs) is of great significance in understanding cellular processes, by modulating protein structure and dynamics. Nowadays, with the rapid growth of protein data at different ''omics'' levels, machine learning models largely enriched the prediction of PTMs. However, most machine learning models only rely on protein sequence and little structural information. The lack of the systematic dynamics analysis underlying PTMs largely limits the PTM functional predictions. In this research, we present two dynamicscentric deep learning models, namely, cDL-PAU and cDL-FuncPhos, by incorporating sequence, structure, and dynamics-based features to elucidate the molecular basis and underlying functional landscape of PTMs. cDLPAU achieved satisfactory area under the curve (AUC) scores of 0.804-0.888 for predicting phosphorylation, acetylation, and ubiquitination (PAU) sites, while cDL-FuncPhos achieved an AUC value of 0.771 for predicting functional phosphorylation (FuncPhos) sites, displaying reliable improvements. Through a feature selection, the dynamics-based coupling and commute ability show large contributions in discovering PAU sites and FuncPhos sites, suggesting the allosteric propensity for important PTMs. The application of cDL-FuncPhos in three oncoproteins not only corroborates its strong performance in FuncPhos prioritization but also gains insight into the physical basis for the functions. The source code and data set of cDL-PAU and cDL-FuncPhos are available at https://github.com/ComputeSuda/PTM_ML.

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