作为一种普遍存在的蛋白酪氨酸磷酸酶，SHP2参与了PD-1/PD-L1介导的肿瘤免疫逃逸，并经历了重大构象变化。因此，它被认为是肿瘤干预的理想靶点。然而，SHP2与PD-1胞内ITIM/ITSM磷酸肽结合的变构机制尚不清楚，这严重阻碍了基于结构的新型抗癌变构抑制剂的开发。在这项工作中，首先基于该知识构建了SHP2的开放和闭合结构模型；接下来，通过弹性网络模型（如高斯网络模型（GNM）、异向网络模型（ANM）和自适应异向网络模型（aANM））研究它们的运动模式；最后，使用神经关系推理分子动力学（NRI-MD）模拟嵌入人工智能（AI）策略，提出了一条可能的变构信号通路。在GNM和ANM中，N-SH2、C-SH2和PTP结构域均展现了明显的动力学划分，而N-SH2/C-SH2区域相对于PTP呈刚性旋转。根据aANM给出的一系列中间快照图，首先确定N-SH2与pY223特异性结合，使D'E环从β-折叠形式转变为无规卷曲，并且C-SH2作为支点完全将N-SH2旋转110°，使其完全远离PTP的原始活性位点。最后，基于NRI-MD采样提出了一条可能的SHP2变构信号传递路径，即R220-R138-T108-R32。这项工作提供了SHP2的可能的变构机制，有助于设计新型的变构抑制剂，并预计将与PD-1单克隆抗体在临床上协同应用。

As a ubiquitous protein tyrosine phosphatase, SHP2 is involved in PD-1/PD-L1 mediated tumor immune escape and undergoes substantial conformational changes. Therefore, it is considered an ideal target for tumor intervention. However, the allosteric mechanisms of SHP2 binding PD-1 intracellular ITIM/ITSM phosphopeptides remain unclear, which greatly hinders the development of novel structure-based anticancer allosteric inhibitors. In this work, the open and closed structural models of SHP2 are first constructed based on this knowledge; next their motion modes are investigated via elastic network models such as the Gaussian network model (GNM), anisotropic network model (ANM) and adaptive anisotropic network model (aANM); and finally, a possible allosteric signaling pathway is proposed using a neural relational inference molecular dynamics (NRI-MD) simulation embedded with an artificial intelligence (AI) strategy. In GNM and ANM, the N-SH2, C-SH2 and PTP domains all exhibit distinct dynamics partitions, and the N-SH2/C-SH2 regions show a rigid rotation relative to PTP. According to a series of intermediate snapshots given by aANM, N-SH2 is first identified with pY223 specifically, inducing a D'E-loop to change from β-sheets to random coils, and then, C-SH2 serves as a fulcrum to drive N-SH2 to rotate 110° completely away from the original active sites of PTP. Finally, a possible allosteric signaling-transfer path for SHP2, namely R220-R138-T108-R32, is proposed based on NRI-MD sampling. This work provides a possible allosteric mechanism of SHP2, which is helpful for the following design of novel allosteric inhibitors and is expected to be used in clinical synergies with PD-1 monoclonal antibody.