Peptide Assembly:Mechanism and Inhibition

由美国国家科学基金会化学结构、动力学和机理B计划（CSDM-B）和生命过程化学提供的CHE-1301032奖授予Michael T.位于圣巴巴拉的加州大学的Bowers将被用于研究肽组装的机制。 这是目前一个非常活跃的研究领域，既因为其基本的重要性，也因为在神经系统疾病中可能的治疗应用。 这些研究将包括低聚物分布的测定，大小选择的低聚物的结构和选择抑制剂对该过程的影响。 将选择肽来测试现有的β折叠形成和最终原纤维化的模型，以及它们在淀粉样蛋白疾病中的可能意义。 实验方法将包括离子迁移谱与质谱，原子力显微镜和透射电子光谱和一个新开发的低聚物尺寸选择红外光谱实验在弗里茨哈伯研究所在柏林，德国。 实验将补充高层次的理论计算，包括DFT和复制交换分子动力学。 抑制剂将包括天然存在的物质，如多酚和专门合成的分子，设计用于选择肽附着。在美国，两种增长最快的主要疾病是阿尔茨海默病和2型糖尿病。 这些看似不同的疾病都有一个共同的特点，即体内通常无害的物质（肽）的组装产生有毒物质：一个过程发生在大脑中，导致阿尔茨海默病，另一个过程发生在胰腺中，导致2型糖尿病。 目前尚不清楚这些通常安全的物种是如何组装成致命的物种的，也不清楚它们组装后如何杀死细胞。 这是一个很难用常规生物化学工具研究的问题，因为常规生物化学工具不能选择特定的组装肽，因此不能告诉它们的结构或毒性。 该提案的主旨是提供一套新的方法，可以进行这种选择，并将这些方法应用于模拟肽系统，以了解一般控制肽组装的因素，然后测试可以阻止这种组装的简单分子。 最后，研究结果将被转化为可以给当地高中的演示文稿，每个Bowers小组成员每年都会访问几所这样的学校进行演示。

The award CHE-1301032 provided by the Chemical Structure, Dynamics and Mechanism-B Program (CSDM-B) and the Chemistry of Life Processes of the National Science Foundation to Professor Michael T. Bowers at the University of California at Santa Barbara will be used to investigate the mechanism of peptide assembly. This is currently a very active area of research both for its fundamental importance and because of possible therapeutic applications in neurological diseases. These studies will include the determination of oligomer distributions, the structures of sized selected oligomers and the effect of select inhibitors on this process. Peptides will be selected to test existing models for beta sheet formation and eventual fibrilization and for their possible implications in amyloid based diseases. Experimental methods will include ion mobility spectrometry coupled with mass spectrometry, atomic force microscopy and transmission electron spectroscopy and a newly developed oligomer size selected infrared spectroscopy experiment constructed at the Fritz Haber Institute in Berlin, Germany. The experiments will be complimented by high level theoretical calculations including both DFT and replica exchange molecular dynamics. Inhibitors will include both naturally occurring substances like polyphenols and specially synthesized molecules designed for select peptide attachment. The two fastest growing major diseases in the US today are Alzheimer's disease and Type 2 Diabetes. These seemingly dissimilar diseases share the common trait of having toxic agents that come from the assembly of ordinarily innocuous agents (peptides) in the body: one process occurring in the brain causing Alzheimer's disease and the other in the pancreas causing Type 2 Diabetes. It isn't clear how these normally safe species assemble into deadly ones nor is it clear how they kill cells once they do assemble. This is a difficult problem to study with the normal tools of biochemistry that can't select specific assembled peptides and hence can't tell their structure or how toxic they are. The thrust of this proposal is to provide a new set of methods that can do this selecting and to apply these methods to model peptide systems to learn the factors that control peptide assembly in general and then test simple molecules that can stop this assembly in its tracks. Finally the results are translated into presentations that can be given to local high schools and each Bowers group member visits several such schools each year to make these presentations.