The role played by conformational changes in enzyme catalysis is controversial. In addition to examining specific enzymes, studying formal models can help identify the conditions under which conformational changes promote catalysis. Here, we present a model demonstrating how conformational changes can break a generic trade-off due to the conflicting requirements of successive steps in catalytic cycles, namely high specificity for the transition state to accelerate the chemical transformation and low affinity for the products to favor their release. The mechanism by which the trade-off is broken is a transition between conformations with different affinities for the substrate. The role of the effector that induces the transition is played by a substrate “handle,” a part of the substrate that is not chemically transformed but whose interaction with the enzyme is nevertheless essential to rapidly complete the catalytic cycle. A key element of the model is the formalization of the constraints causing the trade-off that the presence of multiple states breaks, which we attribute to the strong chemical similarity between successive reaction states—substrates, transition states, and products. For the sake of clarity, we present our model for irreversible one-step unimolecular reactions. In this context, we demonstrate how the different forms that chemical similarities between reaction states can take impose limits on the overall catalytic turnover. We first analyze catalysts without internal degrees of freedom and then show how two-state catalysts can overcome their limitations. Our results recapitulate previous proposals concerning the role of conformational changes and substrate handles in a formalism that makes explicit the constraints that elicit these features. In addition, our approach establishes links with studies in the field of heterogeneous catalysis, where the same trade-offs are observed and where overcoming them is a well-recognized challenge.

中文翻译：

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构象变化在酶催化中的作用

构象变化在酶催化中所起的作用是有争议的。除了检查特定的酶之外，研究形式模型还可以帮助确定构象变化促进催化的条件。在这里，我们提出了一个模型，展示了构象变化如何打破由于催化循环中连续步骤的相互冲突的要求而产生的一般权衡，即过渡态的高特异性以加速化学转化，而产品的低亲和力以有利于其发布。打破这种权衡的机制是对底物具有不同亲和力的构象之间的转变。诱导转变的效应器的作用是由底物“手柄”发挥的，底物“手柄”是底物的一部分，未发生化学转化，但其与酶的相互作用对于快速完成催化循环至关重要。该模型的一个关键要素是约束的形式化，导致多个状态的存在打破了权衡，我们将其归因于连续反应状态（底物、过渡态和产物）之间的强烈化学相似性。为了清楚起见，我们提出了不可逆一步单分子反应的模型。在这种情况下，我们展示了反应状态之间的化学相似性可以采取的不同形式如何对总体催化周转施加限制。我们首先分析没有内部自由度的催化剂，然后展示两种状态催化剂如何克服其局限性。我们的结果概括了之前关于构象变化和底物处理在形式主义中的作用的提议，该形式主义明确了引发这些特征的约束。此外，我们的方法与多相催化领域的研究建立了联系，在该领域观察到相同的权衡，并且克服它们是一个公认的挑战。