Using a charging coordinate in studies of ionization induced partial unfolding
Using a charging coordinate in studies of ionization induced partial unfolding
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DOI：
10.1021/jp061190o
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发表时间：
2006-06-15
影响因子：
3.3
通讯作者：
Warshel, Arieh
中科院分区：
文献类型：
--
作者：
Kato, Mitsunori;Warshel, Arieh
蛋白质中基团的电离有时可能涉及部分解折叠和/或水渗透。不幸的是，由于纳秒 FEP 模拟中未克服激活势垒，微观自由能扰动 (FEP) 方法可能无法捕获相应的结构变化。例如，从在蛋白质内部引入可电离基团的突变实验以及通过微观方法重现相应的 pK(a) 变化的困难来看，这个问题是显而易见的。在这里，我们开发了一种新的通用方法来治疗此类具有挑战性的病例。我们的方法通过增加电离基团的电荷超过其物理值来驱动蛋白质结构变化，从而通过物理一致的过程克服部分展开的障碍。通过评估葡萄球菌核酸酶 Val66Glu 突变体的 pK(a) 说明了我们方法的潜力。在这种情况下，首先证明标准 FEP 方法对该 pK(a) 给出的结果极其令人失望。另一方面，我们的“过度收费”方法给出了更现实的结果。我们相信，本方法代表了蛋白质中可电离残基的 FEP 研究的突破，并期望该策略可用于研究各种具有挑战性的问题，包括氢交换过程的模拟。
The ionization of groups in proteins may sometimes involve a partial unfolding and/or water penetration. Unfortunately the corresponding structural changes might not be captured by microscopic free energy perturbation (FEP) approaches due to activation barriers that are not surmounted in nanosecond FEP simulations. This problem is apparent, for example, from mutation experiments that introduced ionizable groups in protein interiors and from the difficulties to reproduce the corresponding pK(a) changes by microscopic approaches. Here we develop a new general approach for treating such challenging cases. Our approach drives the protein structural change by increasing the charge of the ionized group beyond its physical value and thus overcoming the barriers for the partial unfolding by a physically consistent process. The potential of our approach is illustrated by the evaluation of the pK(a) of the Val66Glu mutant of staphylococcal nuclease. In this case it is first demonstrated that standard FEP approaches give extremely disappointing results for this pK(a). On the other hand, our "overchargning" approach gives a much more realistic result. We believe that the present approach represents a breakthrough in FEP studies of ionizable residues in proteins, and expect this strategy to be useful in studies of a wide range of challenging problems including simulations of hydrogen exchange processes.