Early Events in Protein Folding

描述（由申请人提供）：本提案的总体目标是描述蛋白质折叠的动力学和分子机制。我们试图确定基本过程的特征速率和潜在的分子机制，包括链坍塌、二级结构形成和特定三级相互作用的形成。我们计划解决的基本问题包括：超快折叠蛋白的基本动力学、过渡态结构和折叠机制是什么？能否使超快折叠蛋白在不跨越自由能垒（下坡折叠）的情况下折叠？残余结构在变性状态下的作用是什么，这种结构是否加速了折叠？肽模型和超快折叠子结构域在完整蛋白质的情况下表现出相同的折叠行为吗？这些问题是当前蛋白质折叠文献中激烈审查和辩论的主题。为了回答这些问题，我们建议将实验和模拟紧密结合起来。我们设计了实验方法来定量测试超快折叠蛋白的MD模拟的预测。反过来，我们期望MD模拟能够激发新的实验，或帮助解释实验观察结果。我们期望这种实验和理论之间的密切相互作用对两者都大有裨益，并最终提高我们对蛋白质折叠方式的理解。了解蛋白质如何折叠成其天然的生物活性结构仍然是现代生物学的一个中心问题，对合理的蛋白质设计、蛋白质结构预测和折叠相关的疾病状态具有重要的实际意义。错误折叠蛋白质的聚集和沉积，有时是单点突变的结果，是各种神经退行性疾病的共同特征，如阿尔茨海默病、帕金森病、朊病毒病、亨廷顿病和运动神经元疾病。这项提议的工作将为蛋白质如何折叠以及当它们折叠错误并导致疾病时出现的问题提供新的理解。

DESCRIPTION (provided by applicant): The overall objective of this proposal is to characterize the dynamics and molecular mechanisms of protein folding. We seek to determine the characteristic rates and underlying molecular mechanisms of the fundamental processes, including chain collapse, secondary structure formation, and formation of specific tertiary interactions. The basic questions we plan to address include: What are the fundamental dynamics, transition state structures and folding mechanisms of ultrafast folding proteins? Can ultrafast folding proteins be made to fold without crossing a free energy barrier (downhill folding)? What is the role of residual structure in the denatured state, and does such structure speed folding? Do peptide models and ultrafast folding subdomains exhibit the same folding behavior in the context of the full protein? These questions are the subject of intense scrutiny and debate in the current protein folding literature. We propose a close interaction between experiment and simulation to answer these questions. We have designed experimental approaches to quantitatively test the predictions of MD simulations of ultrafast folding proteins. In turn, we expect MD simulations to motivate new experiments, or help in the interpretation of experimental observables. We expect such a close interplay between experiment and theory to greatly benefit both, and ultimately improve our understanding of how proteins fold. PUBLIC HEALTH RELEVANCE Understanding how a protein folds to its native, biologically active structure continues to be a central problem of modern biology, with important practical consequences for rational protein design, protein structure prediction and folding related disease states. The aggregation and deposition of misfolded proteins, sometimes the consequence of a single point mutation, is a common feature of neurodegenerative disorders as diverse as Alzheimer's disease, Parkinson's disease, prion diseases, Huntington's disease, and motor neuron disease. The proposed work will provide new understanding of how proteins fold, and what goes wrong when they misfold and cause disease.