Molecular dynamics simulations investigate the pathway of substrate entry active site of rhomboid protease
Molecular dynamics simulations investigate the pathway of substrate entry active site of rhomboid protease
复制标题
分子动力学模拟研究菱形蛋白酶底物进入活性位点的途径
DOI：
10.1080/07391102.2018.1517609
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发表时间：
2019-09-02
影响因子：
4.4
通讯作者：
Huang，Xuri
中科院分区：
文献类型：
--
作者：
Zhou，Hua;Yu，Hui;Huang，Xuri
摘要菱形蛋白酶可以催化肽键断裂，参与生命的各个分支的丰富的生物过程，然而，底物进入其活性位点的途径仍然是模糊的。在此，通过分子动力学初步确定了两条可能的途径：一条途径位于Tm 2和Tm 5之间，另一条途径位于Loop 3和Loop 5之间。然后，伞抽样模拟进行调查更可行的途径，为基板进入。结果表明，两条途径的自由能垒沿着是相似的;在途径1中，Trp 236和Trp 157作为关键残基负责结合过程中底物的旋转;在途径2中，在一些重要残基中，残基His 150在底物进入中起着重要作用。进一步结合前面的实验结果，得出衬底倾向于沿沿着进入活性位的结论。这些结果对进一步了解菱形蛋白酶的功能和催化机制具有重要意义。作者：Ramaswamy H. Sarma
Abstract Rhomboid proteases can catalyze peptide bond cleavage and participate in abundant biological processes encompassing all branches of life; however, the pathway for substrate entry into its active site remains ambiguous. Here, the two possible pathways are preliminarily determined through molecular dynamics: One pathway is between Tm2 and Tm5, and the other is between Loop3 and Loop5. Then, the umbrella sampling simulations are performed to investigate the more feasible pathway for substrate entry. The results show that free energy barriers along the two pathways are similar; in the pathway 1, Trp236 and Trp157 as pivotal residues are responsible for the rotation of substrate in the binding process; in the pathway 2, among some important residues, the residue His150 plays an important role in substrate entry. Further, combining with previous experiment results, it is concluded that the substrate is inclined to enter into the active site along pathway 2. Our results are important for further understanding the function and catalysis mechanism of rhomboid proteases. Communicated by Ramaswamy H. Sarma