扩散系数曲线如何降低蛋白质折叠自由能的任意性
How the diffusivity profile reduces the arbitrariness of protein folding free energies
摘要：
蛋白质在其自由能折叠景观中扩散的概念在理论和实验上都取得了丰硕的成果。然而，反应坐标（RC）的选择引入了一个不希望的程度的任意性的问题。我们分析了大量的α-螺旋在明确的水溶剂中的模拟数据，因为它stochandeles折叠和展开。不同RC的自由能分布表现出显着的变化，一些具有激活势垒，其他没有。我们表明，这种变化有预测的折叠动力学的影响不大，如果适当考虑到扩散率的配置文件。这种动力学的准普遍性是合理的RC重新缩放，其中，由于重新参数化不变性的福克-普朗克方程，允许自由能和扩散率的影响组合成一个单一的功能，重新缩放的自由能配置文件。如果我们正确区分包含自然状态知识的RC和那些本质上纯粹是几何的RC，这种重新标度的自由能确实显示出比裸自由能和扩散率分布单独所做的更少的不同RC之间的变化。我们的方法提取扩散率曲线很容易应用于实验单分子时间序列数据，并可能有助于调和冲突时出现的比较结果从不同的实验探针相同的蛋白质。
英文摘要：
The concept of a protein diffusing in its free energy folding landscape has been fruitful for both theory and experiment. Yet the choice of the reaction coordinate (RC) introduces an undesirable degree of arbitrariness into the problem. We analyze extensive simulation data of an alpha-helix in explicit water solvent as it stochastically folds and unfolds. The free energy profiles for different RCs exhibit significant variation, some having an activation barrier, others not. We show that this variation has little effect on the predicted folding kinetics if the diffusivity profiles are properly taken into account. This kinetic quasi-universality is rationalized by an RC rescaling, which, due to the reparameterization invariance of the Fokker-Planck equation, allows the combination of free energy and diffusivity effects into a single function, the rescaled free energy profile. This rescaled free energy indeed shows less variation among different RCs than the bare free energy and diffusivity profiles separately do, if we properly distinguish between RCs that contain knowledge of the native state and those that are purely geometric in nature. Our method for extracting diffusivity profiles is easily applied to experimental single molecule time series data and might help to reconcile conflicts that arise when comparing results from different experimental probes for the same protein.
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