Study protein folding mechanism using a roadmap-based approach

描述(申请人提供)：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。要实现这一目标，了解蛋白质折叠过程的细节是必不可少的。虽然蛋白质能量图景的概念已经建立，但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。我们建议基于我们新的基于路线图的方法开发一个通用的计算方法来理解这个过程。我们基于路线图的方法将给出相对折叠速度，定位折叠途径，强制中间态，偏离途径的中间体，过渡态，并验证结合和折叠之间的协同性。我们的方法将利用路线图(或图)来捕捉目标1中提出的蛋白质构象空间和能量格局的最重要特征，反过来，将从路线图中提取丰富的热力学和动力学信息，并根据目标2中的基于图的工具进行进一步分析。我们最近使用我们新的图论方法增强反应路径算法在预测蛋白质折叠路径方面取得了令人振奋的结果，这是我们基于路线图的方法的一部分。我们希望我们基于路线图的方法将产生折叠机制的全面图景。目标3中的拟议应用将集中在几个小蛋白质上，这将使我们能够学习关于蛋白质折叠机制的以下方面的基本原理：(A)蛋白质折叠的统一特征；(B)隐藏的中间体；(C)“下坡”折叠；(D)结合和折叠之间的协作性。有关折叠过程的信息不仅对于将基因组序列映射到蛋白质结构和功能是不可或缺的，而且在淀粉样蛋白疾病和其他与蛋白质固有紊乱相关的人类疾病中也是重要的。对蛋白质折叠过程的深入了解最终可以为药物设计带来更好的计算模型。 公共卫生相关性：在绘制基因组序列与蛋白质结构和功能的图谱时，了解原子细节的蛋白质折叠过程是必不可少的。蛋白质折叠/展开和错误折叠与淀粉样蛋白疾病和其他与蛋白质固有紊乱有关的人类疾病有关。对蛋白质折叠过程的深入了解最终可以为药物设计带来更好的计算模型。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Understanding protein folding process in atomic detail is indispensible in mapping the genomic sequence onto protein structure and function. Protein folding/unfolding and misfolding are implicated 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.