Computational Biomedicine Section, Institute of Advanced Simulation IAS-5 and Institute of Neuroscience and Medicine INM-9, Forschungszentrum Jülich GmbH , 52425 Jülich, Germany.
The Alexander Silberman Life Science Institute and the Wolfson Center for Applied Structural Biology, The Hebrew University of Jerusalem, Edmond J. Safra Campus at Givat Ram , 91904 Jerusalem, Israel.
J Phys Chem B. 2017 Nov 30;121(47):10648-10656. doi: 10.1021/acs.jpcb.7b10584. Epub 2017 Nov 16.
The NEET proteins are a novel family of iron-sulfur proteins characterized by an unusual three cysteine and one histidine coordinated [2Fe-2S] cluster. Aberrant cluster release, facilitated by the breakage of the Fe-N bond, is implicated in a variety of human diseases, including cancer. Here, the molecular dynamics in the multi-microsecond timescale, along with quantum chemical calculations, on two representative members of the family (the human NAF-1 and mitoNEET proteins), show that the loss of the cluster is associated with a dramatic decrease in secondary and tertiary structure. In addition, the calculations provide a mechanism for cluster release and clarify, for the first time, crucial differences existing between the two proteins, which are reflected in the experimentally observed difference in the pH-dependent cluster reactivity. The reliability of our conclusions is established by an extensive comparison with the NMR data of the solution proteins, in part measured in this work.
NEET 蛋白是一类新型的铁硫蛋白家族，其特征是具有不寻常的三个半胱氨酸和一个组氨酸配位的 [2Fe-2S] 簇。铁氮键的断裂促进了异常簇的释放，与多种人类疾病有关，包括癌症。在这里，对家族中的两个代表性成员（人 NAF-1 和 mitoNEET 蛋白）进行了多微秒时间尺度的分子动力学和量子化学计算，结果表明簇的丢失与二级和三级结构的急剧下降有关。此外，该计算还为簇的释放提供了一种机制，并首次阐明了两种蛋白质之间存在的关键差异，这反映在实验观察到的 pH 依赖性簇反应性差异上。我们的结论通过与溶液蛋白的 NMR 数据进行广泛比较得到了验证，部分数据是在这项工作中测量的。
