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A thermodynamic definition of protein domains

机译：蛋白质结构域的热力学定义

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摘要

Protein domains are conspicuous structural units in globular proteins, and their identification has been a topic of intense biochemical interest dating back to the earliest crystal structures. Numerous disparate domain identification algorithms have been proposed, all involving some combination of visual intuition and/or structure-based decomposition. Instead, we present a rigorous, thermodyna-mically-based approach that redefines domains as cooperative chain segments. In greater detail, most small proteins fold with high co-operativity, meaning that the equilibrium population is dominated by completely folded and completely unfolded molecules, with a negligible subpopulation of partially folded intermediates. Here, we redefine structural domains in thermodynamic terms as cooperative folding units, based on m-values, which measure the coopera-tivity of a protein or its substructures. In our analysis, a domain is equated to a contiguous segment of the folded protein whose m-value is largely unaffected when that segment is excised from its parent structure. Defined in this way, a domain is a self-contained cooperative unit; i.e., its cooperativity depends primarily upon intra-segment interactions, not intersegment interactions. Implementing this concept computationally, the domains in a large representative set of proteins were identified; all exhibit consistency with experimental findings. Specifically, our domain divisions correspond to the experimentally determined equilibrium folding intermediates in a set of nine proteins. The approach was also proofed against a representative set of 71 additional proteins, again with confirmatory results. Our reframed interpretation of a protein domain transforms an indeterminate structural phenomenon into a quantifiable molecular property grounded in solution thermodynamics.
机译：蛋白质结构域是球状蛋白质中显着的结构单元，其鉴定一直是最早的晶体结构引起人们强烈的生化关注的话题。已经提出了许多不同的域识别算法，所有这些算法都涉及视觉直觉和/或基于结构的分解的某种组合。相反，我们提出了一种严格的，基于热力学的方法，将域重新定义为协作链段。更详细地讲，大多数小蛋白以高协同性折叠，这意味着平衡群体由完全折叠和完全展开的分子控制，部分折叠的中间体的亚群可忽略不计。在这里，我们基于m值，以热力学术语将结构域重新定义为协作折叠单元，以测量蛋白质或其子结构的协同作用。在我们的分析中，结构域等同于折叠蛋白的连续片段，当从其亲本结构中切除该片段时，其m值在很大程度上不会受到影响。以这种方式定义的域是一个独立的合作单位；即，其协作性主要取决于段内交互，而不取决于段间交互。通过计算实现此概念，可以识别出一大批具有代表性的蛋白质中的结构域；均与实验结果一致。具体来说，我们的结构域划分对应于一组九种蛋白质中实验确定的平衡折叠中间体。该方法还针对一组代表性的71种其他蛋白质进行了验证，再次得到证实。我们对蛋白质结构域的重新解释将不确定的结构现象转化为基于溶液热力学的可量化分子特性。

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