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。实现这一 因此，了解蛋白质折叠过程的细节至关重要。虽然蛋白质能量的概念 虽然已经建立了生物景观，但生物物理界面临的主要挑战之一是获得 蛋白质折叠过程的直接信息。我们建议开发一个通用的 计算方法基于我们的新的基于路线图的方法来理解这个过程。 我们的一般路线图为基础的方法将给出相对折叠率，定位折叠途径，强制性 中间态，非途径中间体，过渡态，并验证结合之间的协同性 和折叠。我们的方法将利用路线图（或图表）来捕获蛋白质的最重要特征 目标1中提出的构象空间和能量景观，反过来， 将从路线图中提取信息，并使用Aim中提出的基于图形的工具进行进一步分析 2.我们最近在预测蛋白质折叠途径方面获得了有希望的结果，使用我们的新图- 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 我希望我们的路线图为基础的方法将产生一个全面的图片折叠机制。拟议 Aim 3中的应用程序将集中在几个小蛋白质上，这将使我们能够了解基本原理 关于蛋白质折叠机制的以下方面：（a）蛋白质折叠的统一特征;（B）隐藏的 中间;（c）“下坡”折叠;（d）结合和折叠之间的协同性。 折叠过程的信息不仅是基因组序列定位到蛋白质上所必需的 结构和功能，而且在淀粉样蛋白疾病和其他人类疾病相关的重要性。 内在无序的蛋白质对蛋白质折叠过程的深入了解最终可以更好地 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.