Nucleation: The Birth of a New Protein Phase.
Nucleation: The Birth of a New Protein Phase.
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DOI：
10.1016/j.bpj.2015.10.011
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发表时间：
2015-11
影响因子：
3.4
通讯作者：
Wei-Feng Xue
中科院分区：
文献类型：
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作者：
Wei-Feng Xue
成核是引发相变的过程。自世纪末Gibbs关于成核热力学的经典工作以来，对成核过程的研究已经扩展到各种各样的科学领域。到目前为止，成核已经在从生物物理学到宇宙学的学科中进行了研究，这些学科的系统跨越了原子到行星尺度以及更远的尺度（1）。历史上也已知溶液中的蛋白质通过成核形成各种状态和结构（2，3）。在过去的二十年中，蛋白质组装成与许多人类疾病如阿尔茨海默病、帕金森病和II型糖尿病相关的高度有序的淀粉样蛋白原纤维，引发了对理论发展的新兴趣，这导致了蛋白质原纤维组装的新动力学模型（4，5）。随着这些新的发展，成核作用通过成核过程再次在蛋白质生物物理学中占据了重要地位，在成核过程中，蛋白质的过饱和溶液形成由淀粉样原纤维组成的不溶性超分子蛋白质聚集体，淀粉样原纤维由其高度有序的cross-b构象定义（6）。因此，淀粉样蛋白组装将可溶性蛋白质转化为可能与人类疾病相关的不溶性部分，而启动这种相变的成核机制代表了迄今为止尚未解决的具有医学和基本生物物理重要性的过程。在这一期的《生物物理学杂志》中，Kashchiev（7）提出了一个关于成核理论应用于一个简单的一维聚合模型的理论研究，即描述线性和螺旋聚合物形成的Oosawa-Kasai模型。在其均匀成核性能的三个版本的这种一维聚合的热力学和动力学进行了评价。通过这种方法，严格评估了聚合模型的成核行为或缺乏成核行为。推导了模型中的核心尺寸、聚合功、成核速率和成核能垒等关键热力学量的计算公式。在这里，Kashchiev为如何将经典成核理论应用于蛋白质原纤维的形成提供了一个重要的例子。通过展示如何在概念上简单的方式来评估蛋白质原纤维成核的热力学和动力学，他提供了一个关键的观点，将蛋白质聚合的新动力学模型与成核物理化学提供的经典热力学和动力学结果联系起来。通过这项工作，Kashchiev提出了新的挑战，并为解决纤维蛋白聚合和淀粉样蛋白形成机制中的初始分子步骤提供了新的机会。首先，这项工作为研究人员设计新的实验提出了新的挑战，这些实验具有足够的信息内容和分析方法，可用于验证蛋白质成核模型。例如，Kashchiev使用的方法预测了可以观察和测量的固定前核物质（亚核）分布和成核速率。在蛋白质原纤维组装的实验研究中，与其他主要过程（图1中的蓝色和橙子箭头）相比，直接或间接观察成核过程（图1中的红色和紫色箭头）无疑是最具挑战性的。新的实验方法，如基于微流体的测定，荧光方法和多方法组合，允许新的检测早期单体相互作用，单一成核事件，和罕见的prenucleus物种（4，8-10）可以解决分子...
Nucleation is a process that initiates phase transitions. Since the classical work of Gibbs on nucleation thermodynamics at the end of the nineteenth century, research into nucleation processes has been spread into a huge variety of scientific fields. To date, nucleation has been studied in disciplines ranging from biophysics to cosmology in systems spanning atomic to planetary scales and beyond (1). Proteins in solution are also known historically to form a variety of states and structures through nucleation (2, 3). In the past two decades, the assembly of proteins into highly ordered amyloid fibrils associated with numerous human diseases such as Alzheimer’s disease, Parkinson’s disease, and Type II diabetes mellitus has sparked renewed interest in theory development, which has resulted in new kinetic models of protein fibril assembly (4, 5). With these new developments, nucleation has again come to the fore in protein biophysics through the nucleated processes in which supersaturated solutions of proteins form insoluble supramolecular protein aggregates consisting of amyloid fibrils, which are defined by their highly ordered cross-b conformation (6). Thus, amyloid assembly converts soluble proteins into insoluble fractions that can be associated with human diseases, and the nucleation mechanism that initiates this phase transition represents a hitherto unresolved process of medical and fundamental biophysical importance. In this issue of the Biophysical Journal, Kashchiev (7) presents a theoretical study on the application of nucleation theory to a simple onedimensional polymerization model, the Oosawa-Kasai model that describes the formation of linear and helical polymers. The thermodynamics and kinetics of three versions of such one-dimensional polymerization in terms of their homogeneous nucleation properties were evaluated. With this approach, the nucleation behavior of the polymerization models, or lack thereof, was assessed rigorously. Formulae for key thermodynamic quantities such as nucleus size, polymerization work, nucleation rate, and the nucleation energy barrier were derived for the models. Here, Kashchiev sets an important example on how classical nucleation theory can be applied to protein fibril formation. By showing how the thermodynamics and kinetics of protein fibril nucleation can be evaluated in a conceptually straightforward manner, he offers a critical perspective that links new kinetic models of protein polymerization with the classic thermodynamics and kinetics results offered by the physical chemistry of nucleation. With this work, Kashchiev sets new challenges and offers new opportunities toward resolving the initial molecular steps in the mechanism of fibrous protein polymerization and amyloid formation. Firstly, this work sets a renewed challenge for researchers to design new experiments with sufficient information content and analysis approaches that can be used to validate protein nucleation models. For example, the approach used by Kashchiev predicts stationary prenuclei species (subnuclei) distribution and nucleation rates that could be observed and measured. In experimental studies of protein fibril assembly, direct or indirect observations of nucleation processes (red and purple arrows in Fig. 1) are, arguably, the most challenging to achieve compared to the other main processes involved (blue and orange arrows in Fig. 1). New experimental approaches such as microfluidics-based assays, fluorescence methods, and multimethod combinations, which allow novel detection of early monomer interactions, single nucleation events, and rare prenucleus species (4, 8–10) may resolve the molecular …