Thermodynamic prediction of protein neutrality
Thermodynamic prediction of protein neutrality
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DOI：
10.1073/pnas.0406744102
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发表时间：
2005-01-18
影响因子：
11.1
通讯作者：
Arnold, FH
中科院分区：
文献类型：
--
作者：
Bloom, JD;Silberg, JJ;Arnold, FH
我们提出了一个简单的理论，该理论利用热力学参数来预测蛋白质在经过一个或多个随机氨基酸替换后仍保留野生型结构的概率。我们的理论预测，对于大量的替换，蛋白质保留其结构的概率将随替换次数呈指数下降，这种下降的严重程度由结构的特性决定。我们的理论还预测，蛋白质可以通过增加其热力学稳定性来对最初的几次替换获得额外的稳健性。我们通过对晶格蛋白质模型的模拟以及表明它能定量预测先前发表的关于枯草杆菌蛋白酶的实验测量结果和我们自己对TEM1β -内酰胺酶变体的测量结果，验证了我们的理论。我们的工作统一了关于功能蛋白质在序列空间中聚集的观察结果，并为解释蛋白质工程应用中蛋白质对替换的反应提供了基础。
We present a simple theory that uses thermodynamic parameters to predict the probability that a protein retains the wild-type structure after one or more random amino acid substitutions. Our theory predicts that for large numbers of substitutions the probability that a protein retains its structure will decline exponentially with the number of substitutions, with the severity of this decline determined by properties of the structure. Our theory also predicts that a protein can gain extra robustness to the first few substitutions by increasing its thermodynamic stability. We validate our theory with simulations on lattice protein models and by showing that it quantitatively predicts previously published experimental measurements on subtilisin and our own measurements on variants of TEM1 beta-lactamase. Our work unifies observations about the clustering of functional proteins in sequence space, and provides a basis for interpreting the response of proteins to substitutions in protein engineering applications.