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

阿尔茨海默病(AD)是由淀粉样β蛋白多肽(Ab1-42)与金属离子(主要是Cu2+/Cu1+、Zn2+、Fe3+/Fe2+、Fe3+/Fe2+、Fe-和铁血红素)结合而形成的聚集态。总体目标是确定阿尔茨海默病的化学原因或传播步骤。下一个授权期的近期目标建立在以往工作的基础上，并解决了一些尚未得到解答的重要问题。它们都属于基础物理和计算化学领域，应用于具有生物学意义的过程。建议的研究直接涉及铜和铁(血红素)/抗体络合物的结构和氧化还原性质。这些物质会产生活性氧物种(ROS)，在生物系统中会对细胞成分造成损害。我们还研究了抗体与多肽/伪肽以及与其结合的蛋白质之间的相互作用，目的是确定结合亲和力和序列特异性。我们还将模拟神经细胞膜和内皮膜的性质，以及它们与抗体之间的化学和物理相互作用，这些相互作用会导致脂质过氧化和孔洞形成。

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.