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首页> 外文期刊>Journal of Biomolecular Structure and Dynamics >Dynamical footprint of falcipain-2 catalytic triad in hemoglobin-beta-bound state
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Dynamical footprint of falcipain-2 catalytic triad in hemoglobin-beta-bound state

机译：血红蛋白-β-结合状态的falcipain-2催化三联体的动态足迹

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Falcipain-2 (FP-2) is a member of papain family of cysteine proteases and the major hemoglobinase of the hemoglobin detoxification and hemozoin polymerization complex localized in the food vacuole of the plasmodium species. FP-2 is currently gaining clinical significance as the drug target of choice in combating malaria epidemic. Here, a theoretical FP-2/hemoglobin complex has been proposed and the dynamical footprint and energetics of binding have been investigated using molecular and quantum mechanics approaches. The mapped interaction interface comprises residues 34-51 of hemoglobin and cysteine-42/histidine-174/glutamine-36/asparagine-173/204 and subsites S1, S1 ', and S3 of FP-2. In hemoglobin-bound FP-2, asparagine-173 preferentially partners histidine-174, while glutamine-36 is preferred in ligand-free state. Cysteine-42 exhibits dihedral switch from 110 degrees to 30 degrees in free and bound states, respectively, with exclusion of water from the binding core upon hemoglobin binding. Hemoglobin similarly exhibits high occupancy within .2 nm distance with charged amido acid-rich subsites S1 and S3 of FP-2 functioning in tandem to reduce conformational flexibility of hemoglobin and facilitate the formation of a stabilizing anti-parallel beta-sheet between Leucine-172-valine-176 of FP-2 and phenylalanine-45-asparate-47 of hemoglobin and to overcome the + 1.13e + 5 eV activation energy required to optimize the FP-2/hemoglobin-beta conformation that precedes hydrolysis.
机译：Falcipain-2（FP-2）是木瓜蛋白酶的半胱氨酸家族成员，是主要的血红蛋白酶，位于血丝虫种类的食物液泡中，是血红蛋白解毒和血红素聚合复合物的主要组成部分。 FP-2作为对抗疟疾流行的首选药物靶点，目前在临床上具有重要意义。在这里，已经提出了理论上的FP-2 /血红蛋白复合物，并且已经使用分子和量子力学方法研究了结合的动力学足迹和能量学。映射的相互作用界面包含血红蛋白的残基34-51和半胱氨酸-42 /组氨酸-174 /谷氨酰胺-36 /天冬酰胺-173/204以及FP-2的亚位S1，S1'和S3。在与血红蛋白结合的FP-2中，天冬酰胺173优先与组氨酸174结合，而谷氨酰胺36在无配体状态下是优选的。半胱氨酸-42在游离和结合状态下分别显示从110度到30度的二面角转换，在结合血红蛋白时水从结合核心中排除。血红蛋白同样在0.2 nm距离内显示高占有率，带电荷的FP-2富酰胺基酸亚位S1和S3串联发挥作用，以降低血红蛋白的构象柔韧性并促进在Leucine-172之间形成稳定的反平行β-折叠FP-2的-valine-176和血红蛋白的苯丙氨酸-45-天冬氨酸-47，并克服了在水解之前优化FP-2 /血红蛋白-β构象所需的+ 1.13e + 5 eV活化能。

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