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引用次数: 2
摘要
蛋白质的计算机建模包括多种计算工具,旨在获得有关这些生物分子的结构,电子和/或动态信息,捕获对实验方法具有挑战性的机制细节,例如难以捉摸的酶-底物复合物,短寿命中间体和反应过渡态(TS)。本文为读者提供了关于使用硅建模技术来理解碳水化合物活性酶(CAZymes)的复杂催化反应机制的见解,以及在该领域重要的基础理论和概念。我们首先介绍碳水化合物在自然界中的重要性和处理它们的酶,CAZymes,强调它们的碳水化合物底物的构象灵活性。三种常用的硅方法(经典分子动力学(MD),混合量子力学/分子力学(QM/MM)和增强采样技术)描述了非专业读者。最后,我们提供了三个应用这些方法的例子来揭示三种疾病相关的酶的催化机制:β-半乳糖脑苷酶(GALC),负责克拉伯病;α-甘露糖苷β-1,6- n -乙酰氨基葡萄糖转移酶V (MGAT5)参与癌症;O- focusyltransferase 1 (POFUT1),参与多种人类疾病,如白血病和Dowling-Degos病。
In silico modelling of the function of disease-related CAZymes.
In silico modelling of proteins comprises a diversity of computational tools aimed to obtain structural, electronic, and/or dynamic information about these biomolecules, capturing mechanistic details that are challenging to experimental approaches, such as elusive enzyme-substrate complexes, short-lived intermediates, and reaction transition states (TS). The present article gives the reader insight on the use of in silico modelling techniques to understand complex catalytic reaction mechanisms of carbohydrate-active enzymes (CAZymes), along with the underlying theory and concepts that are important in this field. We start by introducing the significance of carbohydrates in nature and the enzymes that process them, CAZymes, highlighting the conformational flexibility of their carbohydrate substrates. Three commonly used in silico methods (classical molecular dynamics (MD), hybrid quantum mechanics/molecular mechanics (QM/MM), and enhanced sampling techniques) are described for nonexpert readers. Finally, we provide three examples of the application of these methods to unravel the catalytic mechanisms of three disease-related CAZymes: β-galactocerebrosidase (GALC), responsible for Krabbe disease; α-mannoside β-1,6-N-acetylglucosaminyltransferase V (MGAT5), involved in cancer; and O-fucosyltransferase 1 (POFUT1), involved in several human diseases such as leukemia and the Dowling-Degos disease.
期刊介绍:
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