Peptide Assembly:Mechanism and Inhibition

由化学结构、动力学和机制B计划(CSDM-B)和国家科学基金会的生命过程化学提供给加州大学圣巴巴拉分校的迈克尔·T·鲍尔斯教授的CHE-1301032奖将用于研究多肽组装的机制。这是目前一个非常活跃的研究领域，既因为它的基本重要性，也因为它可能在神经疾病中的治疗应用。这些研究将包括确定齐聚物的分布、选定齐聚物大小的结构以及选定抑制剂对这一过程的影响。将选择多肽来测试现有的贝塔折叠形成和最终纤化的模型，以及它们在淀粉样蛋白疾病中的可能含义。实验方法将包括离子迁移率光谱与质谱仪、原子力显微镜和透射电子光谱相结合，以及在德国柏林弗里茨·哈伯研究所新开发的低聚物尺寸选择红外光谱实验。这些实验将得到包括密度泛函理论和复制交换分子动力学在内的高水平理论计算的补充。抑制剂将包括自然产生的物质，如多酚，以及为选择多肽结合而专门设计的合成分子。当今美国增长最快的两种主要疾病是阿尔茨海默氏症和2型糖尿病。这些看似不同的疾病有一个共同的特点，那就是有毒物质来自于体内通常无害的物质(多肽)的组装：一个过程发生在大脑中，导致阿尔茨海默氏症，另一个过程发生在胰腺，导致2型糖尿病。目前还不清楚这些通常安全的物种是如何组装成致命物种的，也不清楚一旦它们组装起来，它们是如何杀死细胞的。这是一个很难用常规的生物化学工具来研究的问题，因为它们不能选择特定的组装肽，因此不能分辨它们的结构或毒性有多大。这项建议的主旨是提供一套新的方法来进行这种选择，并将这些方法应用于多肽系统的建模，以了解一般控制多肽组装的因素，然后测试可以阻止这种组装的简单分子。最后，结果会被翻译成报告，可以交给当地的高中，每个鲍尔斯小组的成员每年都会去几所这样的学校做这些报告。

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.