MODELLING THE UNFOLDED STATE OF PROTEINS

蛋白质的变性状态一直是一个引人入胜的话题， 在米尔斯基的提议之后，近60年来的巨大困惑 鲍林认为蛋白质结构理论恰恰是一种 蛋白质变性。鲍林的早期工作之后是开创性的 弗洛里、坦福德和其他许多人的贡献。然而，到目前为止，还有 仍然没有足够详细的变性状态模型 在折叠和装订的计算研究中的实际应用。 我们寻找一种可靠的变性状态的思想，可以用来 计算折叠时溶剂可及表面积的变化 和/或绑定。大多数文学价值都是残留物的表面积， ，处于变性状态，作为其在扩展的Gly-X Gly中的区域 三肽，或偶尔，在一些其他密切相关的化合物中。而当 任何定义明确的状态在形式上都适合用作标准状态， 变性状态经常被视为等同于此 标准状态，通常导致对该地区的严重高估 迷失在折叠或装订上。 解决这个问题的一个明显的方法是刺激 在变性条件下具有所需序列的多肽。然而， 这种模拟的结果将高度敏感地选择 力场。我们建议绕过这个依赖于力场的问题。 通过将答案括在可靠的极端之间，从而提供了一个上限 和下限。一个极端是硬球模型，它只有 排斥力(即排除的体积)，因此暴露出更多 表面比预期的分子能在 变性条件。在另一种极端情况下，可以使用 从折叠的蛋白质中提取的长度有限。这样的区段缺乏 长距离的互动，尽管长距离肯定是真的 相互作用可能参与了决定分子的构象 细分市场。尽管如此，折叠的线段仍可用作 相应的多肽在变性条件下不太可能 更好地保护自己不受溶剂的影响。 初步结果表明，两个极限之间的间隔-硬 球体和折叠蛋白质-可能足够小，可以有效地应用于 本计划项目中提出的结构和热力学研究。

The denatured state of proteins has been a topic of riveting interest and great perplexity for almost six decades, following the proposal of Mirsky and Pauling that a theory of protein structure is precisely a theory of protein denaturation. Pauling's early work was followed by seminal contributions from Flory, Tanford and many others. Yet, to date there is still no model of the denatured state that is sufficiently detailed for practical use in computational studies of folding and binding. We seek a reliable minded of the denatured state that can be used to calculate changes in the solvent accessible surface area upon folding and/or binding. Most literature values take the surface area of a residue, , in the denatured state as being its area in an extended Gly-X Gly tripeptide or, occasionally, in some other closely related compound. While any well-defined state is formally suitable for use as a standard state, the denatured state has all too often been taken to the equivalent to this standard state, resulting typically ina large over-estimate of the area lost on folding or binding. One obvious approach to this problem would be to stimulate athe behavior of a peptide of desired sequence under denaturing conditions. However, the result of such a simulation would be highly sensitive to the choice of force field. We propose to circumvent this force field-dependent problem by bracketing the answer between reliable extremes, thus providing an upper and lower limit. At one extreme is the hard sphere model which has only repulsive forces (i.e. excluded volume), and which therefore exposes more surface than would be expected in a molecule that can self-associate under denaturing conditions. At the other extreme, one can use segments of limited length taken from folded proteins. Such segments are devoid of long range interactions, although it is certainly true that long range interactions may have been involved in determining the conformation of the segment. Nevertheless, folded segments still serve as a useful extreme in that the corresponding peptide under denaturing conditions is unlikely to be better shielded from the solvent. Preliminary results suggest that the interval between the two limits - hard sphere and folded protein-may be small enough to be applied usefully in the structural and thermodynamic studies proposed in this Program Project.