Although electrostatics have long been recognized to play an important role in hydrogen exchange (HX) with solvent, the quantitative assessment of its magnitude in the unfolded state has hitherto been lacking. This limits the utility of HX as a quantitative method to study protein stability, folding and dynamics. Using the intrinsically disordered human protein α-synuclein as a proxy for the unfolded state, we show that a hybrid mean-field approach can effectively compute the electrostatic potential at all backbone amide positions along the chain. From the electrochemical potential a four-fold reduction in hydroxide concentration near the protein backbone is predicted for the C-terminal domain, a prognosis that is in direct agreement with experimentally-derived protection factors from NMR spectroscopy. Thus, impeded HX for the C-terminal region of α-synuclein is not the result of intramolecular hydrogen bonding and/or structure formation.

中文翻译：

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静电在未折叠蛋白质状态下对氢交换的贡献

尽管人们早已认识到静电在与溶剂进行的氢交换（HX）中起着重要的作用，但迄今仍缺乏对其在未折叠状态下强度的定量评估。这限制了HX作为研究蛋白质稳定性，折叠和动力学的定量方法的用途。使用内在无序的人类蛋白质α-突触核蛋白作为未折叠状态的替代物，我们表明杂化平均场方法可以有效地计算沿链的所有主链酰胺位置的静电势。根据电化学势，可预测C端结构域附近蛋白质骨架附近的氢氧化物浓度降低4倍，这一预后与NMR光谱实验得出的保护因子直接一致。因此，