Folding, Mis-Folding and Aggregation of Small Proteins

描述(申请人提供)：合理的药物设计或淀粉样变性疾病的病理只是两个问题，它们的解决需要详细了解蛋白质的化学组成和结构(和功能)之间的关系。本项目描述了通过计算机模拟来探索这种关系的尝试。其目标是仅从蛋白质内部原子之间以及蛋白质与周围环境之间的物理作用力来理解蛋白质的折叠和相互作用。PI扩展了之前的工作，并依赖于他的团队开发的算法，旨在推导描述细胞中蛋白质折叠、聚集和相互作用的基本过程的模型。作为一个例子，PI将在电子计算机上研究两种蛋白质--残基胰凝乳蛋白酶抑制物2和93残基蛋白TOP7折叠成特定形状的机制。这本身就是一项大胆的计算任务，需要进一步的算法进步和大规模并行软件的实现。模拟这些分子，PI将不会推动计算机模拟超越其目前的限制，并建立描述小蛋白质折叠的规则。了解这些规则将为更有效的药物设计方法铺平道路。在第二条线的研究中，PI超越了单一蛋白质，研究了多个A链之间的相互作用及其随后的寡聚作用。他将研究哪些因素比单体状态更有利于低聚物物种，以及点突变和金属离子对低聚物稳定性的影响。由于A聚集体与阿尔茨海默病的神经病理有关，这项研究将有助于加深对该疾病生物发生机制的理解。 公共卫生相关性：小蛋白的折叠、错误折叠和聚集项目叙述性计算机模拟被提出来研究蛋白质折叠成其生物活性形式的过程，以及这些分子错误折叠和随后聚集的条件。这将有助于发展对与错误折叠和聚集相关的疾病的生物发生的理解，并可能导致更有效的药物设计方法。

DESCRIPTION (provided by applicant): Rational drug design or the pathology of amyloid diseases are only two problems whose solution requires a detailed understanding of the relation between chemical composition and structure (and function) of proteins. The present project describes attempts to explore this relationship through computer simulations. The goal is to understand the folding and interaction of proteins solely from the physical forces between the atoms within a protein, and between the protein and the surrounding environment. Extending previous work and relying on algorithms developed in his group, the PI aims at deriving models that describe the fundamental processes of protein folding, aggregation and interaction in a cell. As an example, the PI will study in silico the mechanism by that two proteins, the 64- residue Chymotrypsin Inhibitor 2 and the 93-residue protein TOP7, fold into their specific shape. This is in itself a daring computational task that will require further algorithmic advances and implementation in massively parallel software. Simulating these molecules the PI will not push computer simulations beyond its present limits, and establish rules that describe folding in small proteins. Knowledge of such rules will pave the way to more efficient ways of drug design. In a second line of research the PI goes beyond single proteins and studies the interaction between multiple A chains and their subsequent oligomerization. He will investigate what factors favor oligomeric species over monomeric states, and the effect of point mutations and metal ions on the stability of the oligomers. As A aggregates are connected with the neuropathology of Alzheimer's disease this study will contribute to the developing understanding of the biogenesis of this disease. PUBLIC HEALTH RELEVANCE: Folding, Misfolding and Aggregation of Small Proteins Project Narrative Computer simulations are proposed to study the process by that proteins fold into their biologically active form, and the conditions under that these molecules misfold and subsequently aggregate. This will contribute to the developing understanding of the biogenesis of diseases related to misfolding and aggregation, and could lead to more efficient ways of drug design.