Bioinorganic chemistry of metalloproteins and tetrapyrroles

我们研究计划的基础是金属蛋白和合成类似物的生物无机化学。含金属的蛋白质在生命中占据主导地位。从离子平衡、神经和肌肉活动到结构稳定(通常是锌)到催化活性(例如铁)，各种必需金属都能发挥作用。这些金属必须插入到脱辅基蛋白中，并确保所产生的完整蛋白的结构完整性，以获得最佳的生理活性。细胞的一个关键方面是金属从营养来源吸收后的储存。过渡金属和d-嵌段金属必须与伴侣结合，以避免不必要的和潜在有毒的基于细胞的反应。金属化途径、结合常数、反应机理以及金属化对蛋白质结构的影响是我们关注的焦点。这些研究得到了具有广泛仪器资源的专业知识的支持，以探索生物要求苛刻的分子系统的基本属性。我们的研究利用计算数据来预测金属结合位的光学性质和氧化还原性质。 有三种技术主导了我们的研究： (I)定量分析测量，主要根据电喷雾电离质谱仪(ESI-MS)确定的与平衡、时间和温度相关的性质。(2)确定金属化物种形成、配体配位以及自旋和氧化态的详细光学光谱测量。(Iii)络合物几何和电子结构的计算研究，包括金属蛋白结构和对接的分子动力学，以及配位几何和激发态性质的DFT和TD-DFT方法。 两类金属蛋白和四个吡咯形成了我们方案的核心焦点。 (I)依赖金属活性的蛋白质(具体地说，转铁蛋白、血红素蛋白质、碳酸氢酶和超氧化物歧化酶)。 (Ii)金属硫蛋白，这是一种铜和锌的细胞储存蛋白，随后将这些金属转移到金属酶中，但除此之外，该蛋白还清除有毒金属，最后可以作为细胞的守门人，防止外来金属(如含金属的药物)的入侵。我们建议的研究直接适用于目前灾难性神经疾病的焦点蛋白质错误折叠。我们将利用对金属结合位点的计算研究来了解折叠过程中涉及的特定化学物质。 (Iii)四吡咯是血红素蛋白的辅因子，合成上，作为卟啉和酞菁，从叶绿素中的叶绿素到P450细胞色素中的卟啉和氧处理装置中的卟啉，都具有非常不同的性质。合成的叶绿素类似物是太阳能电池中充当光子收集器的设备的关键。我们的计算指导合成将突出关键的分子因素，以提高光敏剂的活性。

The foundation of our research programme is the bioinorganic chemistry of metalloproteins and synthetic analogs. Metal-containing proteins dominate Life. A wide range of essential metals fulfill roles from ionic balance, nerve, and muscle action to structural stability (often zinc) to catalytic activity (for example iron). These metals must be inserted into the apoprotein and the structural integrity of the resulting holoprotein assured for optimal, physiological activity. A key cellular aspect is the storage of metals following absorption from nutritional sources. Transition and d-block metals must be bound to chaperones to avoid unwanted and potentially toxic cellular-based reactivity. The metalation pathways, binding constants, reaction mechanisms and the structural impact of metallation on proteins are our focus. These studies are supported by expertise with a wide range of instrumental resources to probe the underlying properties of the biologically demanding molecular systems. Our research makes use of computational data to predict optical and redox properties of the metal-binding sites. Three technologies dominate our studies: (i) Quantitative analytical measurements primarily from equilibrium-, time- and temperature-dependent properties determined by electrospray-ionization mass spectrometry (ESI-MS). (ii) Detailed optical spectroscopic measurements that identify metalated speciation, ligand coordination and spin and oxidation states. (iii) Computational studies of the geometric and electronic structures of complexes involving molecular dynamics for metalloprotein structures and docking, and DFT and TD-DFT methods for coordination geometries and excited state properties. Two classes of metalloprotein and the tetrapyrroles form the core focus of our programme. (i) Proteins that are dependent on metals for activity (specifically, transferrin, heme proteins, carbonic anhydrase, and superoxide dismutase). (ii) Metallothionein, a copper and zinc cellular storage protein that subsequently transfers these metals to metalloenzymes, but in addition this protein scavenges for toxic metals, and, finally, can act as a gate-keeper for the cell, guarding against intrusion by xenobiotic metals (such as metal-containing drugs). Our proposed studies are directly applicable to the protein misfolding currently the focus in catastrophic neurological diseases. We will use computational studies of metal-binding sites to understand the specific chemistries involved during folding. (iii) Tetrapyrroles are the cofactors of heme proteins, and synthetically, as porphyrins and phthalocyanines, offer remarkably diverse properties from the chlorins in chlorophylls, to the porphyrins in the P450 cytochromes and in the oxygen processing apparatus. The synthetic chlorophyll analogs are key to devices that can act as photon collectors in solar cells. Our computationally-guided synthesis will highlight key molecular factors to enhance photosensitizer activity.