Integrating experiment and theory for predicting protein folding pathways and str

描述(申请人提供)：蛋白质折叠和动态是许多生物学活动不可或缺的一部分，包括伴侣作用、蛋白质降解、淀粉样蛋白疾病和衰老。我们的目标是将实验和计算研究相结合，以产生对蛋白质折叠行为的预测性理解，无论它们是自然发生的、设计的、展开的还是本质上的无序的。我们的？分析方法将过渡态识别为大的、类似于自然的状态，并与其他数据一起，认为折叠是通过顺序稳定的过程发生的。目标1描述了我们计划的测试，即这种机制是否适用于整个通路，特别是早期部分。同时，我们将推进我们的统一框架，只使用序列作为输入来预测路径和结构。虽然该方法仅基于蛋白质化学的基本原理，但其精度可与最好的MD模拟相媲美。我们将提供不同蛋白质的高分辨率数据来测试我们和其他人的模拟，包括合作者DESRES。目标2描述了我们将如何调查展开状态在自然条件下是否压缩。FRET和MD模拟的结果是肯定的，而小角X射线散射则表明情况并非如此。我们将探索这种令人困惑的差异的根源，这对折叠机制、MD模拟的有效性和生物热力学都有影响。目的3总结了我们提出的天然蛋白质折叠和具有复杂折叠动力学的新型设计折叠的比较。确定复杂动力学的起源既挑战了我们的理解，也有助于改进设计算法。

DESCRIPTION (provided by applicant): Protein folding and dynamics are integral to many biological activities, including chaperone action, protein degradation, amyloid diseases and aging. Our goal is to combine experimental and computational studies to produce a predictive understanding of folding behavior for proteins, independent of whether they are naturally occurring, designed, unfolded, or intrinsically disordered. Our ? analysis method identifies transition states as large and native-like and, along with other data, argues that folding occurs via a process of sequential stabilization. Aim 1 describes our planned tests of whether this mechanism applies to the whole pathway, especially the early portions. In parallel, we will advance our unifying framework for predicting both pathways and structure using only the sequence as input. Although the method is based only on basic principles of protein chemistry, it has an accuracy comparable to the best MD simulations. We will provide high-resolution data for different proteins to test our simulations and those of others, including DESRES, a collaborator. Aim 2 delineates how we will investigate whether the unfolded state compacts under native conditions. FRET and MD simulations indicate yes, whereas small angle X-ray scattering indicates otherwise. We will probe the origins of this perplexing discrepancy that has implications to folding mechanisms, the validity of MD simulations, and biothermodynamics. Aim 3 summarizes our proposed comparison of the folding of naturally occurring proteins and novel designed folds with complex folding kinetics. Identifying the origin of the complex kinetics both challenges our understanding and can help improve design algorithms.