Metal-Peptide and Peptide-Peptide Interactions of Relevance to Alzheimer's Disease

阿尔茨海默病（AD）是由淀粉样蛋白β肽（Ab或Ab(1-42)）与金属离子（主要是Cu2+/Cu1+、Zn2+、Fe3+/Fe2+、铁和铁血红素）相关的聚集形式引起的。总体目标是确定AD的化学原因或传播步骤。下一个拨款期的直接目标建立在以前的工作基础上，并解决一些重要的尚未解答的问题。所有这些都是在基础物理和计算化学领域应用于生物兴趣的过程。提出的研究直接针对Cu和Fe（血红素）/Ab配合物的结构和氧化还原性质。它们产生活性氧（ROS），在生物系统中对细胞成分造成损害。我们还讨论了Ab与肽/假肽之间的相互作用，以及与之结合的蛋白质，目的是确定结合亲和力和序列特异性。我们还将模拟神经元和内皮膜的性质，以及它们与Ab之间导致脂质过氧化和孔形成的化学和物理相互作用。适当的理论和计算方法的应用。对于较小的系统，我们使用基于高水平量子力学的方法，使我们能够确定温度和水环境对结构和性质的影响。这些可以计算气相，更重要的是，水相自由能差，从而产生酸度常数，平衡常数和电化学还原电位。涉及化学变化的较大系统采用混合量子力学-分子力学（QM/MM）方法处理，而那些不涉及化学变化的系统，如肽、肽复合物和脂质双层的溶液结构，则采用经验分子动力学（MD）模拟处理。我们的团队拥有所有所需方法的软件和丰富的经验。

Alzheimer's disease(AD) is caused by an aggregated form of the amyloid beta peptide (Ab, or Ab(1-42)) in association with metals ions, primarily, Cu2+/Cu1+, Zn2+, Fe3+/Fe2+, ferro- and ferriheme. The overall objective is to determine the chemical causes or propagating steps of AD. The immediate objectives for the next granting period build on previous work and address some important as yet unanswered questions. All are in the realm of basic physical and computational chemistry applied to processes of biological interest. The proposed research directly addresses the structure and redox properties of Cu and Fe(heme)/Ab complexes. These generate reactive oxygen species (ROS) that in bological systems cause damage to cell components. We also address the interactions between Ab and peptides/pseudopeptides, and proteins that bind to it, with the aim of determining binding affinities and sequence specificities. We will also simulate the nature of neuronal and endothelial membranes, and the chemical and physical interactions between them and Ab that result in lipid peroxidation and pore formation. Appropriate theoretical and computational methodology is applied. For smaller systems, we use high level quantum mechanics-based methods that enable us to determine the effect of temperature and the aqueous environment on structures and properties. These permit the calculation of gaseous-phase, and more importantly, aqueous phase free energy differences that in turn yield acidity constants, equilibrium constants and electrochemical reduction potentials. Larger systems that involve chemical changes are treated by mixed quantum mechanical-molecular mechanical (QM/MM) methods, and those that do not, like solution structures of peptides, peptide complexes, and lipid bilayers, are treated by empirical Molecular Dynamics (MD) simulations. Our group has the software and extensive experience with all of the required methodologies.