Repeat Proteins; Stability, Folding Kinetics & Evolution

描述（由申请人提供）：精细分子结构的形成是生物系统的标志，导致酶网络、调节复合物、膜信号传导和包装系统、支架网络等。组装的指令被编码在分子本身中。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，理解这些指令可能会导致合理地操纵疾病机制。一个相对简单但同样壮观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。单结构域蛋白质在全或无反应中折叠。这种显著的耦合现象对于避免生物学中的错误折叠/部分折叠状态可能是重要的，但它使折叠过程的实验研究复杂化，掩盖中间体，过程和路线沿着通往天然状态的道路。这项研究使用了一系列线性对称重复蛋白质，这些蛋白质显示了球状蛋白质的所有特征，但在很大程度上， 降低问题的复杂性，并允许最近邻模型被应用于量化的能量耦合，基础上的协同性。这种内部对称性还允许测试和参数化详细的动力学机制，包括平行路径成核和传播步骤。这些分析模式将应用于含有重复序列的α螺旋和β折叠，以测量协同性和成核动力学过程，并确定它们的结构起源。使用最近鉴定的长度可变的重复序列组， 重复序列的大小及其与相邻序列的界面将与协同性项相关。此外，我们将描绘的序列特征，调节长度在这组蛋白质，并探讨结构和能量的特点"高ID重复蛋白质序列和它们的关系，共有序列。

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.