Unraveling the differences of the hydrolytic activity of Trypanosoma cruzi trans-sialidase and Trypanosoma rangeli sialidase: a quantum mechanics-molecular mechanics modeling study.
Unraveling the differences of the hydrolytic activity of Trypanosoma cruzi trans-sialidase and Trypanosoma rangeli sialidase: a quantum mechanics-molecular mechanics modeling study.
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揭示克氏锥虫转唾液酸酶和兰吉锥虫唾液酸酶水解活性的差异：量子力学-分子力学建模研究。
DOI：
10.1021/jp412294r
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Roitberg,AdrianE
中科院分区：
文献类型：
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作者：
Bueren-Calabuig,JuanA;Pierdominici-Sottile,Gustavo;Roitberg,AdrianE
恰加斯病，也称为美洲锥虫病，是一种致命的慢性疾病，目前影响中美洲和南美洲1000多万人。克氏锥虫(T。克鲁兹（TcTS）是这种寄生虫存活的关键酶：来自宿主的唾液酸被转移到锥虫的细胞表面糖蛋白上，从而避开宿主的免疫系统。另一方面，唾液酸酯酶。rangeli（TrSA）是一种严格的水解酶，不具有反式唾液酸酶活性，与TcTS具有70%的序列同源性。因此，TcTS和TrSA代表了一个很好的框架来理解如何在非常相似的结构下实现不同的催化活性。通过量子力学-分子力学（QM/MM, SCC-DFTB/Amberff99SB）计算和伞形采样模拟，研究了TcTS和TrSA的水解机理，并计算了这些反应的自由能谱。这些结果，加上我们之前的计算研究，能够解释唾液酸酶的催化机制，并描述活性位点的细微差异如何使TrSA成为严格的水解酶，而TcTS是更有效的反式唾液酸酶。
Chagas’ disease, also known as American trypanosomiasis, is a lethal, chronic disease that currently affects more than 10 million people in Central and South America. Thetrans-sialidase fromTrypanosoma cruzi(T. cruzi, TcTS) is a crucial enzyme for the survival of this parasite: sialic acids from the host are transferred to the cell surface glycoproteins of the trypanosome, thereby evading the host’s immune system. On the other hand, the sialidase ofT. rangeli(TrSA), which shares 70% sequence identity with TcTS, is a strict hydrolase and shows notrans-sialidase activity. Therefore, TcTS and TrSA represent an excellent framework to understand how different catalytic activities can be achieved with extremely similar structures. By means of combined quantum mechanics–molecular mechanics (QM/MM, SCC-DFTB/Amberff99SB) calculations and umbrella sampling simulations, we investigated the hydrolysis mechanisms of TcTS and TrSA and computed the free energy profiles of these reactions. The results, together with our previous computational investigations, are able to explain the catalytic mechanism of sialidases and describe how subtle differences in the active site make TrSA a strict hydrolase and TcTS a more efficienttrans-sialidase.