球状蛋白质中恒定m值、变性状态崩溃和残基依赖的转变中点的分子起源
Molecular origin of constant m-values, denatured state collapse, and residue-dependent transition midpoints in globular proteins
摘要：
实验表明，对于许多两态折叠分子，其自然态自由能DG_ND（[C]）随变性剂浓度[C]的变化呈线性变化。斜率m = dDG_ND（[C]）/d[C]几乎是常数。m值与自然态（N）和变性态（D）之间的表面积差有关，它应该是DR_g ^[2]的函数，DR_g ^[2]是D态和N态之间的回转半径平方差。单分子实验表明，随着[C]的减小，变性态经历了一个平衡塌缩转变，这意味着m也应该是[C]依赖的。我们解决了恒定的m值和[C]依赖的Rg变化之间的难题，使用粗粒度的蛋白质L表示的分子模拟，和分子转移模型，其中的平衡折叠可以准确地计算为变性剂浓度的函数。我们发现，在很大的变性剂浓度范围内（> 3 M），m值是一个常数，而在强复性条件下（< 3 M），它取决于[C]。在[C]> 3 M以上，m值是一个常数，因为对m贡献最大的骨架基团的表面积的[C]依赖性变化在变性状态下相对较窄。主链的掩埋引起[C]< 3 M以下的显著表面积变化，导致变性状态下的塌陷。个别残基的过渡中点变化显著，即使整体折叠可以被描述为全或无过渡。由于有利的残基-溶剂相互作用的丧失以及肽内相互作用强度随[C]降低而随之增加而导致的塌陷。这些相互作用不均匀地分布在蛋白L的整个天然结构中。
英文摘要：
Experiments show that for many two state folders the free energy of the native state DG_ND([C]) changes linearly as the denaturant concentration [C] is varied. The slope, m = d DG_ND([C])/d[C], is nearly constant. The m-value is associated with the difference in the surface area between the native (N) and the denatured (D) state, which should be a function of DR_g^2, the difference in the square of the radius of gyration between the D and N states. Single molecule experiments show that the denatured state undergoes an equilibrium collapse transition as [C] decreases, which implies m also should be [C]-dependent. We resolve the conundrum between constant m-values and [C]-dependent changes in Rg using molecular simulations of a coarse-grained representation of protein L, and the Molecular Transfer Model, for which the equilibrium folding can be accurately calculated as a function of denaturant concentration. We find that over a large range of denaturant concentration (> 3 M) the m-value is a constant, whereas under strongly renaturing conditions (< 3 M) it depends on [C]. The m-value is a constant above [C]> 3 M because the [C]-dependent changes in the surface area of the backbone groups, which make the largest contribution to m, is relatively narrow in the denatured state. The burial of the backbone gives rise to substantial surface area changes below [C]< 3 M, leading to collapse in the denatured state. The midpoint of transition of individual residues vary significantly even though global folding can be described as an all-or-none transition. Collapse driven by the loss of favorable residue-solvent interactions and a concomitant increase in the strength of intrapeptide interactions with decreasing [C]. These interactions are non-uniformly distributed throughout the native structure of protein L.
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