酶作用机理的图形变换
Graph Transformation for Enzymatic Mechanisms
摘要：
动机：酶的设计是具有挑战性的，因为它对于使医学和工业应用中的化学合成更有效，更具成本效益和环境友好。虽然这个复杂问题的几个方面是计算机辅助的，但催化机制的起草，即酶要实现的化学步骤和中间状态的规范，在很大程度上留给了人类的专业知识。因此，以能够实现其计算构建和设计的方式捕获多步催化的特定化学的能力是高度期望的，并且同样会影响其机制未知的现有酶促反应的阐明。结果：我们用图变换的数学框架来表达化学中规则和反应的区别。我们从M-CSA数据库（一个酶促机制的精选库）中获得了大约1000条氨基酸侧链化学规则。使用图形转换，我们能够提出数百个假设的催化机制，大量的不相关的反应在Rhea数据库。我们分析了这些机制，发现它们以化学健全的方式结合了各种已知的多步机制中的各个步骤，表明可以通过计算构建合理的催化新机制。
英文摘要：
Motivation: The design of enzymes is as challenging as it is consequential for making chemical synthesis in medical and industrial applications more efficient, cost-effective and environmentally friendly. While several aspects of this complex problem are computationally assisted, the drafting of catalytic mechanisms, i.e. the specification of the chemical steps-and hence intermediate states-that the enzyme is meant to implement, is largely left to human expertise. The ability to capture specific chemistries of multi-step catalysis in a fashion that enables its computational construction and design is therefore highly desirable and would equally impact the elucidation of existing enzymatic reactions whose mechanisms are unknown. Results: We use the mathematical framework of graph transformation to express the distinction between rules and reactions in chemistry. We derive about 1000 rules for amino acid side chain chemistry from the M-CSA database, a curated repository of enzymatic mechanisms. Using graph transformation we are able to propose hundreds of hypothetical catalytic mechanisms for a large number of unrelated reactions in the Rhea database. We analyze these mechanisms to find that they combine in chemically sound fashion individual steps from a variety of known multi-step mechanisms, showing that plausible novel mechanisms for catalysis can be constructed computationally.
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