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首页> 外文期刊>Journal of Molecular Biology >Structural origins of high apparent dielectric constants experienced by ionizable groups in the hydrophobic core of a protein.
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Structural origins of high apparent dielectric constants experienced by ionizable groups in the hydrophobic core of a protein.

机译：蛋白质疏水核中的可电离基团经历的高表观介电常数的结构起源。

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The side chains of Lys66, Asp66, and Glu66 in staphylococcal nuclease are fully buried and surrounded mainly by hydrophobic matter, except for internal water molecules associated with carboxylic oxygen atoms. These ionizable side chains titrate with pK(a) values of 5.7, 8.8, and 8.9, respectively. To reproduce these pK(a) values with continuum electrostatics calculations, we treated the protein with high dielectric constants. We have examined the structural origins of these high apparent dielectric constants by using NMR spectroscopy to characterize the structural response to the ionization of these internal side chains. Substitution of Val66 with Lys66 and Asp66 led to increased conformational fluctuations of the microenvironments surrounding these groups, even under pH conditions where Lys66 and Asp66 are neutral. When Lys66, Asp66, and Glu66 are charged, the proteins remain almost fully folded, but resonances for a few backbone amides adjacent to the internal ionizable residues are broadened. This suggests that the ionization of the internal groups promotes a local increase in dynamics on the intermediate timescale, consistent with either partial unfolding or increased backbone fluctuations of helix 1 near residue 66, or, less likely, with increased fluctuations of the charged side chains at position 66. These experiments confirm that the high apparent dielectric constants reported by internal Lys66, Asp66, and Glu66 reflect localized changes in conformational fluctuations without incurring detectable global structural reorganization. To improve structure-based pK(a) calculations in proteins, we will need to learn how to treat this coupling between ionization of internal groups and local changes in conformational fluctuations explicitly.
机译：葡萄球菌核酸酶中的Lys66，Asp66和Glu66的侧链完全被疏水物质掩埋并包围，除了与羧基氧原子相关的内部水分子外。这些可电离的侧链的pK（a）值分别为5.7、8.8和8.9。为了通过连续静电学计算重现这些pK（a）值，我们以高介电常数处理了该蛋白质。我们已经通过使用NMR光谱法研究了这些高表观介电常数的结构起源，以表征对这些内部侧链电离的结构响应。即使在Lys66和Asp66为中性的pH条件下，用Lys66和Asp66取代Val66也会导致围绕这些组的微环境构象波动增加。当Lys66，Asp66和Glu66带电时，蛋白质几乎保持完全折叠，但邻近内部可电离残基的一些骨架酰胺的共振变宽。这表明内部基团的电离促进了中间时间尺度上动力学的局部增加，这与残基66附近的螺旋1的部分展开或主链涨落相一致，或者与在位置66处带电侧链的涨落不大相符。位置66。这些实验证实内部Lys66，Asp66和Glu66报告的高表观介电常数反映了构象波动的局部变化，而不会引起可检测的整体结构重组。为了改善蛋白质中基于结构的pK（a）计算，我们将需要学习如何处理内部基团电离与构象波动的局部变化之间的这种耦合。

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