Computer modelling for copper centres in metalloenzymes

铜广泛存在于生物系统中。它结合到蛋白质中，调节光合作用中的电子传递、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等一系列功能。在其他地方，铜与一系列疾病有关，而基于铜的药物作为治疗剂正在积极研究中。蛋白质及其含铜活性部位的分子水平描述对于理解决定功能的因素至关重要，但在原子水平上获取信息是困难的。生物无机化学的特点一直是应用一系列间接(如光谱)和直接(如X射线衍射)技术来探测其通常前所未有的结构性质。理论方法已经并将继续发挥重要作用。铜物种，特别是在氧化+2状态下，表现出明显的电子效应引起的扭曲。这种金属的d电子在结构和能量上都是非无辜的。因此，大多数计算研究涉及某种形式的量子力学(QM)方法，假设这些电子效应不能用更简单的方法处理。然而，量子方法是非常计算密集型的，而且一个完整的蛋白质分子有太多的原子，所以QM计算很难处理。另一种方法是使用配位场理论(LFT)模拟d电子效应。LFT自1929年问世以来，具有经验性的优势，因此速度非常快。与经典的计算机模拟方法分子力学(MM)相结合，配位场分子力学(LFMM)提供了与QM相同的结果，但速度快数千倍。LFMM模型已成功地应用于小的铜配合物。这项提议寻求将这一成功扩展到与蛋白质结合的铜。铜金属酶有五种类型：类型1、类型2、类型3、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某些重要性质，如氧化还原电势。氧化还原过程是至关重要的，但它们的建模是复杂的，因为我们必须采样所有能量可及构象的贡献。这种广泛的计算超出了质量管理方法的范围，但完全在LFMM的能力范围之内。

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.