Repeat Proteins; Stability, Folding Kinetics & Evolution

描述（由申请人提供）：复杂分子结构的形成是生物系统的一个标志，导致酶网络、调节复合体、膜信号和包装系统、脚手架网络和。组装指令被编码在分子内部。理解如何阅读这些指令是现代生物学和现代医学的一个主要目标，理解这些指令可能导致对疾病机制的合理操纵。一个相对简单但同样引人注目的自组装过程是蛋白质折叠问题。了解蛋白质折叠的规则、速率和机制将有助于解释生物学的各个方面，包括与蛋白质错误折叠和聚集有关的疾病状态。蛋白质折叠的核心特征之一是协同性。单域蛋白在全有或无反应中折叠。这种显著的耦合现象可能对避免生物学中的错误折叠/部分折叠状态很重要，但它使折叠过程的实验研究复杂化，掩盖了中间产物、过程和通往天然状态的路线。提出的研究使用了一系列线性对称重复蛋白，它们显示了球状蛋白的所有特征，但很大程度上

DESCRIPTION (provided by applicant): The formation of elaborate molecular structures is a hallmark of biological systems, resulting in enzyme networks, regulatory complexes, membrane signaling and packaging systems, scaffolding networks, and . The instructions for assembly are encoded within the molecules themselves. Understanding how to read these instructions is a major goal in modern biology and in modern medicine, where understanding may lead to rational manipulation of disease mechanisms. One relatively simple yet no less spectacular self-assembly process is the protein folding problem. Understanding the rules, rates, and mechanisms of protein folding would help interpret all aspects of biology, including disease states relating to protein misfolding and aggregation. One of the central features of protein folding is cooperativity. Single-domain proteins fold in all-or-none reactions. This remarkable coupling phenomenon is likely to be important for avoiding misfolded/partly folded states in biology, but it complicates experimental studies of the folding process, masking intermediates, processes, and routes along the way to the native state. The proposed research uses a series of linear symmetric repeat proteins that display all the features of globular proteins, but greatly reduce the complexity of the problem, and allow nearest-neighbor models to be applied to quantify the energetic coupling that underlies cooperativity. This internal symmetry also permits detailed kinetic mechanisms to be tested and parameterized, including parallel pathway nucleation and propagation steps. These modes of analysis will be applied alpha helix and beta sheet containing repeats to measure cooperativity and nucleation kinetic processes and determine their structural origins. Using a recently identified length-variable set of repeats, the size of the repeats and their interfaces with their neighbors will be correlated to cooperativity terms. Further, we will delineate the sequence features that modulate length in this group of proteins, and explore the structural and energetic features of "high-ID repeat protein sequences and their relation to consensus sequences.