中文摘要：

目的研究cADPR从CD38活性口袋解离的过程中配体和受体间的相互作用,并寻找接近真实条件的蛋白结构模型。方法采用拉伸分子动力学的方法模拟cADPR从CD38活性口袋解离的过程。在cGDPR和CD38晶体复合物基础上进行修改,得到cADPR和CD38的复合物;再用动力学优化得到平衡稳定的cADPR和CD38复合物结构;最后施加一个简谐势促使cADPR从活性口袋解离。对解离过程中所施加外力进行监测,计算对比拉伸过程和平衡过程中氨基酸残基的波动情况。结果与结论得到了cADPR解离过程中的一系列蛋白构象。发现cADPR与Trp189、Glu146、Glu226以及Ser126、Arg127的作用是抑制cADPR离去的主要作用。在克服了这些作用之后,cADPR还要克服一些稍弱的水桥作用,最终才能完全离开活性口袋。上述残基在拉伸过程中波动幅度较大,也证明了这些残基在解离过程中的重要性。实验结果加深了对CD38结构和功能的关系及其与底物的相互作用机制的理解,为抑制剂的设计提供了信息。

英文摘要：

To study the interactions between cADPR and human CD38 and obtain protein models during the process of dissociation,cADPR was pulled out from the active pocket of CD38 through a steered molecular dynamics simulation.The structure of cADPR-CD38 complex was built by modifying the X-ray crystal structure of cGDPR-CD38 complex.Firstly,traditional molecular dynamics simulation was carried out to get the minimized and equilibrated starting point for further simulation.Then time-dependent external forces were applied to cADPR to facilitate its dissociation from the protein.A series of CD38 conformations was obtained through the dynamic trajectory.The rupture force profile and the leaving trajectory revealed that the largest resistance of unbinding came from the interactions between cADPR and Trp189,Glu146,Glu226,Ser126 as well as Arg127 residues of CD38.Moreover,some water bridges between cADPR and the residues produced the second force peak.The RMSF of the residues also proved the importance of these residues.The results provided information about the protein′s flexibility and its response to the dissociation of the ligand.