4.7 Article

Molecular Interaction Mechanism of a 14-3-3 Protein with a Phosphorylated Peptide Elucidated by Enhanced Conformational Sampling

期刊

JOURNAL OF CHEMICAL INFORMATION AND MODELING
卷 60, 期 10, 页码 4867-4880

出版社

AMER CHEMICAL SOC
DOI: 10.1021/acs.jcim.0c00551

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资金

  1. JSPS KAKENHI [16K05517, 16K18526, JP20H03229]
  2. HPCI System Research Project [hp190017, hp190018, hp190027, hp200025, hp200063, hp200090]
  3. JSPS [24118008, 16K14711]
  4. Cooperative Research Program of the Institute for Protein Research, Osaka University [CR-19-05, CR-20-05]
  5. Japan Agency for Medical Research and Development, AMED
  6. Grants-in-Aid for Scientific Research [16K18526, 24118008, 16K14711, 16K05517] Funding Source: KAKEN

向作者/读者索取更多资源

Enhanced conformational sampling, a genetic-algorithm-guided multidimensional virtual-system coupled molecular dynamics, can provide equilibrated conformational distributions of a receptor protein and a flexible ligand at room temperature. The distributions provide not only the most stable but also semistable complex structures and propose a ligand-receptor binding process. This method was applied to a system consisting of a receptor protein, 14-3-3 epsilon, and a flexible peptide, phosphorylated myeloid leukemia factor 1 (pMLF1). The results present comprehensive binding pathways of pMLF1 to 14-3-3 epsilon. We identified four thermodynamically stable clusters of MLF1 on the 14-3-3 epsilon surface and free-energy barriers among some clusters. The most stable cluster includes two high-density spots connected by a narrow corridor. When pMLF1 passes the corridor, a salt-bridge relay (switching) related to the phosphorylated residue of pMLF1 occurs. Conformations in one high-density spot are similar to the experimentally determined complex structure. Three-dimensional distributions of residues in the intermolecular interface rationally explain the binding constant changes resulting from the alanine mutation experiment for the residues. We also performed a simulation of nonphosphorylated peptide and 14-3-3 epsilon, which demonstrated that the complex structure was unstable, suggesting that phosphorylation of the peptide is crucially important for binding to 14-3-3 epsilon.

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