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.

铜在生物系统中广泛发现。结合到蛋白质中，它介导了各种功能，例如光合作用中的电子传输，二氧化酶激活（氧化酶，单加氧酶和二氧酶活性），超氧化物降解和氧气转运。在其他地方，铜涉及一系列疾病，而基于铜的药物则作为治疗剂正在积极研究。蛋白质及其含铜的活性位点的分子水平描述对于理解确定功能但在原子水平上获取信息的因素至关重要。生物无机化学始终以间接电池（例如光谱）和直接（例如X射线衍射）技术的应用来探测其通常前所未有的结构特性的特征。理论方法扮演并继续发挥了重要作用。铜种，尤其是在其氧化+2状态下，表现出由电子效应引起的明显扭曲。金属的D电子在结构和大力上是“非自然的”。因此，大多数计算研究都涉及某种形式的量子机械方法（QM）方法，即无法使用更简单的方法处理这些电子效应。但是，量子方法是非常密集的，并且完整的蛋白质分子具有太多的原子，无法进行QM计算。另一种方法是使用配体场理论（LFT）对D电子效应进行建模。 LFT自1929年以来就一直存在，具有经验性，因此非常快。与经典的计算机建模方法分子力学（MM）相结合，配体场分子力学（LFMM）与QM相同，但速度更快。 LFMM模型已成功应用于小铜络合物。该提议旨在将这一成功扩展到与蛋白质结合的铜。铜金属酶位点有五个变体：类型1，类型2，类型3，CUA和CU3。前两个是单核的，而后三则是多核。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某些重要特性（例如氧化还原电位）。氧化还原过程至关重要，但它们的建模很复杂，因为我们必须从所有能量可访问的构象中采样贡献。如此广泛的计算超出了QM方法的范围，但远远超出了LFMM的功能。