Applications and Development of Methodologies for Designing Hybrid Catalysts.

催化剂是一种能提高反应速率而不被消耗的物质。在该项目中，有机金属催化剂（含有金属中心的有机催化剂）和生物分子催化剂（例如酶）特别令人感兴趣。这两类催化剂具有互补的特性，当前项目的目的是通过将金属中心嵌入酶中来将它们联合收割机结合，从而产生混合催化剂。这个想法带来的挑战是找到一种具有结合位点的合适的酶，该结合位点可以容纳有机金属络合物，并且随后微调混合催化剂对于所需反应的催化能力。一般来说，我们希望研究的酶的结合位点还没有进化到含有金属，因此包含金属中心将对酶和有机金属催化剂的结构和反应性产生不可预见的影响。该项目的作用是预测这些结构和反应性的变化，然后修改原始系统以获得所需的反应性。这种基于结构的分子设计方法被称为理性设计，其中周围的残基（以及因此的分子结构）基于其已知的性质和方向而突变。系统的化学和结构特性的知识是通过计算建模获得的，这使我们能够可视化系统并预测它将如何对某些化学修饰作出反应。为此，我们使用了一系列的计算方法，包括低层次的方法（分子力学），以分析结构的变化;和高层次的方法（如量子力学），以分析系统的化学性质的变化，如激活势垒高度。大系统，如酶，是太昂贵了，计算，用量子力学方法处理，因此混合量子力学/分子力学（QM/MM）方法被用来研究所得的混合催化剂的反应性。有机化合物催化剂被用于广泛的工业过程，最显着的是在精细化学品和药物的生产。然而，与酶相比，这些化合物催化反应的速率和相应的周转数（即每个催化剂产生的产物量）非常小。使用混合催化剂的优点之一将是增加对反应机理的控制，这导致更快的速率。此外，在混合催化剂中，人们可能能够获得对反应特异性的更大控制;这意味着不再需要保护基团（用于阻止有机金属催化中发生的副反应）。通过减少副反应的机会，我们减少了生产给定量的实际产品所需的起始物料的量。因此，混合催化剂提供了以比传统有机金属催化剂更有效的方式进行化学挑战性合成的可能性。这种更高的效率是通过减少所需催化剂的量、减少所需反应步骤的数目和增加所需产物的百分产率来实现的。使用混合催化剂，我们可以以更少的成本获得更多的产品-这在经济和环境方面都是有意义的。

A catalyst is a substance that increases the rate at which a reaction occurs without being consumed. In this project organometallic catalysts (organic catalysts that contain a metal centre) and biomolecular catalysts (e.g. enzymes) are of particular interest. These two classes of catalysts have complementary characteristics and the aim of the current project is to combine these by embedding the metal center into an enzyme, resulting in a hybrid catalyst. The challenge that this idea invites is to find an appropriate enzyme with a binding site that can accommodate an organometallic complex and subsequently to fine-tune the catalytic ability of the hybrid catalyst for the desired reaction. In general, the binding sites of the enzymes we wish to investigate have not evolved to contain metals and thus the inclusion of the metal center will have unforeseeable implications on the structure and reactivity of both the enzyme and the organometallic catalyst. The role of this project is to predict what these changes in structure and reactivity will be and then to modify the original system to obtain the desired reactivity. This structure-based approach of designing molecules is known as rational design, whereby the surrounding residues (and consequently the molecular architecture) are mutated based on their known properties and orientation. The knowledge of the chemical and structural properties of the system is gained through computational modeling, which allows us to visualize the system and predict how it will react to certain chemical modifications. For this purpose we use a range of computational methods, including low-level methods (molecular mechanics) in order to analyze structural changes; and high-level methods (such as quantum mechanics) in order to analyze changes in the chemical properties of the system, such as activation barrier heights. Large systems, such as enzymes, are far too expensive, computationally, to be treated with quantum mechanical methods, thus a hybrid quantum mechanical/molecular mechanical (QM/MM) method is employed to study the reactivity of the resulting hybrid catalyst.Organometallic catalysts are used in a wide range of industrial processes; most notably in the production of finechemicals and pharmaceuticals. However, compared to enzymes, the rate at which these compounds catalyze reactions and the corresponding turnover numbers (i.e. amount of product produced per catalyst) is quite small. One of the advantages of using hybrid catalysts will be in the increase of the control of the reaction mechanism, which leads to faster rates. Furthermore, in the hybrid catalyst one may be able to obtain greater control over the specificity of the reaction; this implies that protecting groups (used to stop side reactions occurring in organometallic catalysis) are no longer necessary. By reducing the chance of side reactions we decrease the amount of starting material required to produce a given quantity of the actual product. Thus hybrid catalysts offer the possibility of performing chemically challenging syntheses in a much more efficient manner than is possible with traditional organometallic catalysts. This greater efficiency is achieved through a reduction in the amount of catalyst required, a reduction in the number of reactions steps required and an increase in the percentage yield of the desired product. With hybrid catalysts we get more product for less - which makes sense both economically and environmentally.