Modeling Catalysis in Allosteric Enzymes: Capturing Conformational Consequences
Modeling Catalysis in Allosteric Enzymes: Capturing Conformational Consequences
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DOI：
10.1007/s11244-021-01521-1
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发表时间：
2021-11-09
影响因子：
3.6
通讯作者：
Paton，Robert S.
中科院分区：
文献类型：
--
作者：
Klem，Heidi;McCullagh，Martin;Paton，Robert S.
对酶机制的更深入理解有助于发现生物制剂的新靶点，开发生物催化转化和从头酶设计。使用量子力学（QM）的潜力，如密度泛函理论的方法，使复杂的多步酶的机制进行研究，往往在定量的细节。然而，活性和非活性催化形式之间的酶构象的动态相互转换，涉及的长度和时间尺度无法访问QM治疗，提出了一个艰巨的挑战，为发展的计算模型变构调制酶。我们提出了一个概述的酶催化，酶变构，和大规模的构象变化的方法使用QM，QM/MM，MM潜力的挑战，多态模型的关键概念。结构聚类是一个有价值的方法，桥梁分子动力学，构象采样的MM潜力和量子化学簇模型的催化突出。与此讨论特别相关的是结构变构，它是构象后果的范例。在这里，一个很好的特点变构酶，咪唑甘油磷酸合酶，是用来展示多种构象的重要性，并引导一个新的方向，定性的理解和定量建模的酶催化。
Greater understanding of enzymatic mechanisms aids the discovery of new targets for biologics, the development of biocatalytic transformations, and de novo enzyme design. Methods using quantum mechanical (QM) potentials, such as density functional theory, have enabled complex multistep enzymatic mechanisms to be studied, often in quantitative detail. Nevertheless, the dynamic interconversion of enzyme conformations between active and inactive catalytic forms, involving length- and timescales inaccessible to QM treatments, presents a formidable challenge for the development of computational models for allosterically modulated enzymes. We present an overview of the key concepts underlying multistate models of enzyme catalysis, enzyme allostery, and the challenge that large-scale conformational changes pose for methods using QM, QM/MM, and MM potentials. Structural clustering is highlighted as a valuable approach to bridge molecular dynamics conformational sampling of MM potentials and quantum chemical cluster models of catalysis. Particularly relevant to this discussion is structural allostery, which serves as the exemplar of conformational consequences. Here, a well-characterized allosteric enzyme, imidazole glycerol phosphate synthase, is used to showcase the importance of multiple conformations and guide a new direction for qualitative understanding and quantitative modeling in enzyme catalysis.