Study protein folding mechanism using a roadmap-based approach

项目摘要 我们的长期目标是将基因组序列映射到蛋白质结构和功能上。要做到这一点 目标，了解蛋白质折叠过程的细节是必不可少的。虽然蛋白质能量的概念 景观已经建立，生物物理界面临的关键挑战之一是获得 关于蛋白质折叠过程的原子细节的直接信息。我们建议开发一种通用的 基于我们基于路线图的新方法的计算方法来理解这一过程。 我们一般的基于路线图的方法将给出相对折叠速度，定位折叠路径，这是必须的 中间态、旁路中间体、过渡态，并验证了结合之间的协同性 然后折叠起来。我们的方法将利用路线图(或图表)来捕捉蛋白质的最重要特征 目标1中提出的构象空间和能量格局，反过来又具有丰富的热力学和动力学。 信息将从路线图中提取，并按照AIM中的建议使用基于图表的工具进行进一步分析 2.我们最近在使用我们的新图形预测蛋白质折叠路径方面取得了有希望的结果- 理论方法增强了反应路径算法，这是我们基于路线图的方法的一部分。我们 预计我们基于路线图的方法将产生折叠机制的全面图景。建议数 在AIM 3中的应用将集中在几个小蛋白质上，这将使我们能够学习基本原理 关于蛋白质折叠机制的以下几个方面：(A)蛋白质折叠的统一特征；(B)隐藏 中间；(C)“下坡式”折叠；(D)结合和折叠之间的协同作用。 有关折叠过程的信息不仅是将基因组序列映射到蛋白质中不可缺少的信息 结构和功能，但也重要的淀粉样蛋白疾病和其他相关的人类疾病 本质上无序的蛋白质。对蛋白质折叠过程的深入了解最终可以带来更好的 药物设计的计算模型。

Project Summary Our long-term objective is to map the genomic sequence onto protein structure and function. To achieve this goal, understanding the details of protein folding process is essential. Although the concept of a protein energy landscape has been established, one of the key challenges confronting the biophysical community is to obtain the direct information on protein folding process in atomic detail. We propose to develop a general computational approach based on our novel roadmap-based method to understand this process. Our general roadmap-based approach will give relative folding rates, locate folding pathways, obligatory intermediate states, off-pathway intermediates, transition states, and verify the cooperativity between binding and folding. Our approach will utilize a roadmap (or a graph) to capture most important features of protein conformation space and energy landscape as proposed in Aim 1, in turn, rich thermodynamic and kinetic information will be extracted from the roadmap and further analyzed by graph-based tools as proposed in Aim 2. We have recently obtained promising results in predicting protein folding pathways using our novel graph- theoretical approach enhanced reaction-path algorithm, which is part of our roadmap-based approach. We expect our roadmap-based approach will yield a comprehensive picture of folding mechanism. The proposed applications in Aim 3 will focus on several small proteins, which will allow us to learn fundamental principles regarding the following aspects of protein folding mechanism: (a) unifying features in protein folding; (b) hidden intermediate; (c) "downhill" folding; (d) cooperativity between binding and folding. Information concerning folding process is not only indispensible in mapping the genomic sequence onto protein structure and function, but also important in amyloid diseases and other human diseases associated with intrinsically disordered proteins. A deeper understanding of protein folding process can ultimately lead to better computational models for drug design.