MODELLING THE UNFOLDED STATE OF PROTEINS

蛋白质的变性状态一直是一个令人感兴趣的话题， 巨大的困惑近六十年来，继米尔斯基的建议， 和鲍林认为蛋白质结构理论 蛋白质变性 鲍林的早期工作之后， 来自弗洛里、坦福德和其他许多人的贡献。 然而，迄今为止， 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。 我们寻求变性状态的可靠头脑，可以用来 计算折叠时溶剂可及表面积的变化 和/或绑定。 大多数文献值取残留物的表面积， 在变性状态下，作为其在延伸的Gly-X Gly中的面积， 三肽或偶尔在一些其他密切相关的化合物中。 而 任何明确定义的状态在形式上都适合用作标准状态， 变性状态经常被认为是与此相当的， 标准状态，通常导致对面积的大幅高估 在折叠或装订时丢失。 解决这个问题的一个明显的方法是刺激动物的行为， 所需序列的肽在变性条件下。 但 这种模拟的结果将对选择 力场 我们建议绕过这个力场依赖的问题 通过将答案置于可靠的极端之间，从而提供一个上限， 下限。 一个极端是硬球模型， 排斥力（即排除体积），因此暴露更多 表面比预期的分子，可以自我关联下 变性条件。 在另一个极端，可以使用 从折叠的蛋白质中提取的有限长度。 这样的片段是没有的。 长程相互作用，尽管长程相互作用 相互作用可能参与了决定构象的 片段 尽管如此，折叠段仍然作为一个有用的极端， 相应的肽在变性条件下不太可能 能更好地与溶剂隔离。 初步结果表明，两个极限之间的间隔-硬 球体和折叠的蛋白质-可以足够小，以有效地应用于 结构和热力学研究提出了这个计划项目。

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.