Using Schematic Models to Understand the Microscopic Basis for Inverted Solubility in γD-Crystallin
Using Schematic Models to Understand the Microscopic Basis for Inverted Solubility in γD-Crystallin
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DOI：
10.1021/acs.jpcb.9b07774
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发表时间：
2019-11-28
影响因子：
3.3
通讯作者：
Charbonneau, Patrick
中科院分区：
文献类型：
--
作者：
Altan, Irem;Khan, Amir R.;Charbonneau, Patrick
相反的溶解度--通过冷却使晶体熔化--在少数蛋白质中观察到，如碳氧血红蛋白C和γ D-晶状体蛋白。在人γ D-晶状体蛋白中，该现象与第23个残基（脯氨酸）突变为苏氨酸、丝氨酸或缬氨酸有关。一种提出的微观机制需要在诱变后增加表面疏水性。最近的晶体结构的双突变体，包括P23 T突变允许更仔细的调查这一建议。在这里，我们首先测量γ D-晶状体蛋白的各种突变体结构的表面疏水性，并辨别在第23个残基突变后疏水性没有显著增加。然后，我们调查的溶解度反转制度与示意性补丁粒子模型，包括三个变量的温度依赖性补丁能量之一：两个疏水效应，和一个更通用的性质。我们的结论是，虽然由于疏水效应的溶解度反转可能是可能的，显微镜证据支持它在γ D-晶状体蛋白是弱的。更一般地说，我们发现溶解度反转需要补丁强度和它们的温度依赖性组件之间的良好平衡，这可以解释为什么反转的溶解度是不常见的蛋白质。我们还发现，温度依赖性的相互作用只有一个可以忽略不计的影响液-液相边界的γ D-晶体蛋白，与以前的实验观察。
Inverted solubility-melting a crystal by cooling-is observed in a handful of proteins, such as carbomonoxy hemoglobin C and gamma D-crystallin. In human gamma D-crystallin, the phenomenon is associated with the mutation of the 23rd residue, a proline, to a threonine, serine, or valine. One proposed microscopic mechanism entails an increase in surface hydrophobicity upon mutagenesis. Recent crystal structures of a double mutant that includes the P23T mutation allow for a more careful investigation of this proposal. Here, we first measure the surface hydrophobicity of various mutant structures of gamma D-crystallin and discern no notable increase in hydrophobicity upon mutating the 23rd residue. We then investigate the solubility inversion regime with a schematic patchy particle model that includes one of three variants of temperature-dependent patch energies: two of the hydrophobic effect, and one of a more generic nature. We conclude that, while solubility inversion due to the hydrophobic effect may be possible, microscopic evidence to support it in gamma D-crystallin is weak. More generally, we find that solubility inversion requires a fine balance between patch strengths and their temperature-dependent component, which may explain why inverted solubility is not commonly observed in proteins. We also find that the temperature-dependent interaction has only a negligible impact on liquid-liquid phase boundaries of gamma D-crystallin, in line with previous experimental observations.