Computer modelling for copper centres in metalloenzymes

金属酶中铜中心的计算机建模

• 批准号: BB/E008135/1
• 负责人: Robert James Deeth
• 金额: $ 27.37万
• 依托单位: University of Warwick
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2007
• 资助国家: 英国
• 起止时间: 2007 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FE008135%2F1
• 关键词: Computer; modelling; copper; centres; metalloenzymes

Copper is found extensively in biological systems. Bound into proteins, it mediates a wide range of functions such as electron transport in photosynthesis, dioxygen activation (oxidase, monooxygenase and dioxygenase activity), superoxide degradation and oxygen transport. Elsewhere, copper is implicated in a range of diseases while copper-based drugs are under active investigation as therapeutic agents. A molecular level description of the protein and its copper-containing active site is crucial to understanding the factors which determine function but obtaining information at the atomic level is difficult. Bioinorganic chemistry has always been characterised by the application of a battery of indirect (e.g. spectroscopic) and direct (e.g. X-ray diffraction) techniques to probe their often unprecedented structural properties. Theoretical methods have played, and continue to, play an important role. Copper species, especially in their oxidised +2 state, display pronounced distortions arising from electronic effects. The metal's d electrons are structurally and energetically 'non-innocent'. Consequently, most computational studies involve some form of quantum mechanical (QM) approach on the assumption that these electronic effects cannot be treated using simpler methods. However, quantum approaches are extremely compute-intensive and a complete protein molecule has too many atoms for a QM calculation to be tractable. An alternative method is to model the d electron effects using ligand field theory (LFT). LFT has been around since 1929 and has the advantage of being empirical and thus very fast. Coupled to the classical computer modelling method molecular mechanics (MM), ligand field molecular mechanics (LFMM) delivers the same result as QM but thousands of times faster. The LFMM model has been successfully applied to small copper complexes. This proposal seeks to extend this success to copper bound to proteins. Copper metalloenzyme sites come in five variants: Type 1, Type 2, Type 3, CuA and Cu3. The first two are mononuclear while the latter three are multinuclear. This project will develop LFMM parameters for computing the structures of these sites in complete protein systems as well as certain important properties like the redox potential. Redox processes are vital but their modelling is complicated since we must sample the contributions from all energetically accessible conformations. Such extensive calculations are beyond the scope of QM approaches but well within the capabilities of the LFMM.

铜广泛存在于生物系统中。它与蛋白质结合，介导多种功能，例如光合作用中的电子传递、双氧激活（氧化酶、单加氧酶和双加氧酶活性）、超氧化物降解和氧运输。在其他地方，铜与一系列疾病有关，而铜基药物作为治疗剂正在积极研究中。蛋白质及其含铜活性位点的分子水平描述对于理解决定功能的因素至关重要，但获得原子水平的信息很困难。生物无机化学的特点始终是应用一系列间接（例如光谱）和直接（例如 X 射线衍射）技术来探测其通常前所未有的结构特性。理论方法已经并将继续发挥重要作用。铜物质，特别是在氧化的+2状态下，表现出由电子效应引起的明显扭曲。金属的 d 电子在结构上和能量上都是“非无辜的”。因此，大多数计算研究都涉及某种形式的量子力学（QM）方法，假设这些电子效应无法使用更简单的方法来处理。然而，量子方法的计算量极大，并且完整的蛋白质分子具有太多原子，使得 QM 计算难以处理。另一种方法是使用配体场论 (LFT) 模拟 d 电子效应。 LFT 自 1929 年以来就已出现，其优点是基于经验，因此速度非常快。与经典计算机建模方法分子力学 (MM) 相结合，配体场分子力学 (LFMM) 提供与 QM 相同的结果，但速度快数千倍。 LFMM 模型已成功应用于小型铜配合物。该提案旨在将这一成功扩展到与蛋白质结合的铜。铜金属酶位点有五种变体：1 型、2 型、3 型、CuA 和 Cu3。前两个是单核的，后三个是多核的。该项目将开发 LFMM 参数，用于计算完整蛋白质系统中这些位点的结构以及氧化还原电位等某些重要特性。氧化还原过程至关重要，但其建模很复杂，因为我们必须对所有能量可及的构象的贡献进行采样。如此广泛的计算超出了 QM 方法的范围，但完全在 LFMM 的能力范围内。