title: A systematic molecular dynamics approach to the study of peptide Keap1-Nrf2 protein-protein interaction inhibitors and its application to p62 peptides.
abstract: Protein-protein interactions (PPIs) as drug targets have been gaining growing interest, though developing drug-like small molecule PPI inhibitors remains challenging. Peptide PPI inhibitors, which can provide informative data on the PPI interface, are good starting points to develop small molecule modulators. Computational methods combining molecular dynamics simulations and binding energy calculations could give both the structural and the energetic perspective of peptide PPI inhibitors. Herein, we set up a computational workflow to investigate Keap1-Nrf2 peptide PPI inhibitors and predict the activity of novel sequences. Furthermore, we applied this method to investigate p62 peptides as PPI inhibitors of Keap1-Nrf2 and explored the activity change induced by the phosphorylation of serine. Our results showed that because of the unfavorable solvation effects, the binding affinity of the phosphorylated p62 peptide is lower than the Nrf2 ETGE peptide. Our research results not only provide a useful method to investigate the Keap1-Nrf2 peptide inhibitors, but also give a good example to show how to incorporate computational methods into the study of peptide PPI inhibitors. Besides, applying this method to p62 peptides provides a detailed explanation for the expression of cytoprotective Nrf2 targets induced by p62 phosphorylation, which may benefit the further study of the crosstalk between the Keap1-Nrf2 pathway and p62-mediated selective autophagy.
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China. youqidong@gmail.com jiangzhengyucpu@163.com.
authors.forename: Meng-Chen
authors.initials: MC
authors.lastname: Lu
authors.forename: Zhen-Wei
authors.initials: ZW
authors.lastname: Yuan
authors.forename: Yong-Lin
authors.initials: YL
authors.lastname: Jiang
authors.forename: Zhi-Yun
authors.initials: ZY
authors.lastname: Chen
authors.forename: Qi-Dong
authors.initials: QD
authors.lastname: You
authors.forename: Zheng-Yu
authors.initials: ZY
authors.lastname: Jiang
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D055808:Drug Discovery; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D051267:NF-E2-Related Factor 2 / Q000737:chemistry* / Q000378:metabolism; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D010766:Phosphorylation; D011485:Protein Binding / Q000187:drug effects; D021281:Quantitative Structure-Activity Relationship; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C072437:P62 peptide; D010455:Peptides