The specific regulation of PTPN18 protein to three HER2 phospho-peptides has been studied by molecular dynamics simulations and free energy calculations. The results revealed that the three HER2 phospho-peptides binding to the PTPN18 catalytic domain is energetically favorable due to substrate specificity of PTPN18, and moreover, the PTPN18 protein have significantly higher affinity to pY1248 peptide (−45.22 kcal/mol) than that of pY1112 (−25.3 kcal/mol) and pY1196 (−31.86 kcal/mol) peptides. Further, the binding of HER2 phospho-peptides to PTPN18 have also caused the closure of WPD-loop with the decrease of the centroid distances between the P-loop and the WPD loop. The WPD-loop closure of PTPN18 relates directly to the new hydrogen bond and hydrophobic interaction formations between the residues Tyr62, Asp64, Val65, Ala231, Arg235, and Ala273 in PTPN18 and Tyr(PO3) in the HER2 phospho-peptides, which suggests that these key residues would contribute to the specific regulation of PTPN18 to the substrates. The correlation analysis revealed the allosteric communication networks from the pY binding loop to the WPD loop through the structural change and the residue interactions in PTPN18. These results will be helpful to understand the specific regulation through the allosteric communication network in the PTPN18 catalytic domain.

中文翻译：

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PTPN18对HER2磷酸肽特异性调控的分子动力学模拟研究

已经通过分子动力学模拟和自由能计算研究了 PTPN18 蛋白对三种 HER2 磷酸肽的特异性调节。结果表明，由于 PTPN18 的底物特异性，与 PTPN18 催化结构域结合的三种 HER2 磷酸肽在能量上是有利的，此外，PTPN18 蛋白对 pY1248 肽的亲和力（-45.22 kcal/mol）显着高于 pY1112。 (-25.3 kcal/mol) 和 pY1196 (-31.86 kcal/mol) 肽。此外，HER2 磷酸肽与 PTPN18 的结合也导致了 WPD 环的闭合，同时 P 环和 WPD 环之间的质心距离减小。PTPN18 的 WPD 环闭合直接与残基 Tyr62、Asp64、Val65、Ala231、Arg235、和 PTPN18 中的 Ala273 和 HER2 磷酸肽中的 Tyr(PO3)，这表明这些关键残基将有助于 PTPN18 对底物的特异性调节。相关性分析揭示了通过 PTPN18 中的结构变化和残基相互作用从 pY 结合环到 WPD 环的变构通信网络。这些结果将有助于理解通过 PTPN18 催化域中变构通信网络的具体调控。