标题：Study on the interactions of Smac mimetics with XIAP-BIR3 domain by docking and molecular dynamics simulations
作者：Ling, B.;Zhang, R.;Wang, Z.;Liu, Y.;Liu, C.
作者机构：[Ling, B] School of Chemistry and Chemical Engineering, Shandong University, Jinan, Shandong 250100, China;[ Zhang, R] Northwest Institute of Plateau 更多
通讯作者地址：[Liu, YJ]Shandong Univ, Sch Chem & Chem Engn, Jinan 250100, Shandong, Peoples R China.
来源：Journal of theoretical & computational chemistry
关键词：binding free energy;Inhibitor of apoptosis protein (IAP);molecular docking;molecular dynamics simulations;Smac mimetics
摘要：Upon receiving an apoptotic stimulus, the mature mitochondrial protein second mitochondria-derived activator of caspases (Smac)/direct IAP-binding protein with low PI (DIABLO), which could be released from mitochondria into the cytosol together with cytochrome C, specifically binds to inhibitor of apoptosis proteins (IAPs) and relieves the inhibitory effect of caspase, thus promotes cell death. Some artificial small molecules (called Smac mimetics) can mimic the N-terminal four residues Ala1-Val2-Pro3-Ile4 (AVPI) sequence of mitochondrial protein Smac, and competitively bind to X-linked inhibitor of apoptosis protein baculoviral IAP repeats (XIAP-BIR3) domain with caspase-9, which leads to the removal of the inhibition of caspase-9 by XIAP and induce apoptosis. To gain an insight into the nature of XIAP-BIR3 domain recognizing Smac mimetics, we used docking and molecular dynamics simulations methods to study four representative Smac mimetics. The docking results show that the orientations of these backbones of ligands are identical with that of AVPI in the binding pocket. Each ligand corresponds to two competitive conformations, which are called extended and bended conformations. The results of molecular dynamics simulations show that the extended conformation is more stable, and the calculations of energy decomposition reveal that the residue Thr308 makes the strongest interaction with XIAP-BIR3. In addition, Asp309, Glu314, and Trp323 are indispensable for XIAP-BIR3 recognizing and binding Smac mimetics.