Key Lab of Colloid and Interface Chemistry, Ministry of Education, School of Chemistry and Chemical Engineering, Shandong University, Jinan, Shandong 250100, China.
J Mol Graph Model. 2010 Nov;29(3):354-62. doi: 10.1016/j.jmgm.2010.09.011. Epub 2010 Oct 25.
X-linked IAP can bind caspase-9 and inhibit its activity. Mitochondrial protein Smac/DIABLO can also interact with XIAP and relieve the inhibition on caspase-9 to induce apoptosis. A series of artificial Smac mimetics have been used to mimic the Smac N-terminal tetrapeptide AVPI to bind to XIAP-BIR3, but these structural diverse mimetics exhibited distinct binding affinities. To get an insight into the binding nature and optimize the structures, molecular docking and dynamics simulations were used to study the binding of XIAP-BIR3 with three groups of Smac mimetics. The docking results reveal that these Smac mimetics anchored on the surface groove of XIAP-BIR3 and superimposed well with AVPI. The modifications on the seven-membered ring of bicyclic core segment do not strengthen the binding affinity, while a benzyl introduced to the five-membered ring is favorable to the binding. Molecular dynamics simulations on three typical systems show that these complexes are very stable. Hydrogen bonds between the bicyclic core segment and Thr308 play critical roles in maintaining the stability of complex. The binding free energies calculated by MM_PBSA method are consistent with the experimental results.
X 连锁凋亡抑制蛋白（XIAP）可以结合半胱氨酸蛋白酶-9（caspase-9）并抑制其活性。线粒体蛋白 Smac/DIABLO 也可以与 XIAP 相互作用，解除对 caspase-9 的抑制，诱导细胞凋亡。一系列人工 Smac 类似物已被用于模拟 Smac N 端四肽 AVPI 与 XIAP-BIR3 的结合，但这些结构多样的类似物表现出不同的结合亲和力。为了深入了解结合性质并优化结构，使用分子对接和动力学模拟研究了 XIAP-BIR3 与三组 Smac 类似物的结合。对接结果表明，这些 Smac 类似物锚定在 XIAP-BIR3 的表面凹槽上，并与 AVPI 很好地重叠。二环核心片段的七元环上的修饰并没有增强结合亲和力，而引入到五元环上的苄基有利于结合。对三个典型系统的分子动力学模拟表明，这些复合物非常稳定。二环核心片段和 Thr308 之间的氢键在维持复合物稳定性方面起着关键作用。MM_PBSA 方法计算的结合自由能与实验结果一致。
