Protein stability promotes evolvability
Protein stability promotes evolvability
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DOI：
10.1073/pnas.0510098103
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发表时间：
2006-04-11
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;Labthavikul, ST;Arnold, FH
使蛋白质能够如此容易地进化以执行各种生化任务的生物物理特性在很大程度上是未知的。在这里，我们表明，蛋白质的进化能力是由额外的稳定性所赋予的突变鲁棒性增强。我们使用模型晶格蛋白的模拟来证明额外的稳定性如何通过允许蛋白质接受更广泛的有益突变来增加进化性，同时仍然折叠到其天然结构。我们证实了这一观点实验突变边缘稳定和热稳定的细胞色素P450 BM 3的变体。稳定亲本的突变体更有可能表现出新的或改进的功能。只有稳定的P450亲本可以耐受赋予新活性所需的高度不稳定突变，如羟基化药物naplecen。我们的工作建立了蛋白质稳定性和进化之间的关键联系。我们表明，我们可以利用这种联系来发现蛋白质的功能，我们建议自然进化如何做同样的事情。
The biophysical properties that enable proteins to so readily evolve to perform diverse biochemical tasks are largely unknown. Here, we show that a protein's capacity to evolve is enhanced by the mutational robustness conferred by extra stability. We use simulations with model lattice proteins to demonstrate how extra stability increases evolvability by allowing a protein to accept a wider range of beneficial mutations while still folding to its native structure. We confirm this view experimentally by mutating marginally stable and thermostable variants of cytochrome P450 BM3. Mutants of the stabilized parent were more likely to exhibit new or improved functions. Only the stabilized P450 parent could tolerate the highly destabilizing mutations needed to confer novel activities such as hydroxylating the antiinflammatory drug naproxen. Our work establishes a crucial link between protein stability and evolution. We show that we can exploit this link to discover protein functions, and we suggest how natural evolution might do the same.