Inferring stabilizing mutations from protein phylogenies: application to influenza hemagglutinin.
Inferring stabilizing mutations from protein phylogenies: application to influenza hemagglutinin.
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DOI：
10.1371/journal.pcbi.1000349
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发表时间：
2009-04
影响因子：
4.3
通讯作者：
Glassman MJ
中科院分区：
文献类型：
--
作者：
Bloom JD;Glassman MJ
影响序列进化的一种选择压力是蛋白质需折叠得足够稳定以执行其生物学功能。我们提出了一个概念框架，解释了这一要求如何导致特定氨基酸突变在进化过程中被固定的概率取决于其对蛋白质稳定性的影响。我们从数学上对该框架进行形式化，以开发一种贝叶斯方法，用于从已知系统发育的同源蛋白质序列推断单个突变对稳定性的影响。这种方法能够预测已发表的实验测量的突变稳定性效应（ΔΔG值），其准确性超过了最先进的物理化学建模程序以及基于序列的共识方法。作为进一步的测试，我们使用系统发育推断方法来预测流感血凝素的稳定突变。我们将这些突变引入血凝素基因有缺陷的温度敏感型流感病毒中，并通过实验证明其中一些突变使病毒能够在更高温度下生长。因此，我们的工作描述了一种强大的预测稳定突变的新方法，该方法甚至可成功应用于像血凝素这样的大型复杂蛋白质。这种方法还在系统发育学和可通过实验测量的蛋白质特性之间建立了数学联系，有可能为更准确地分析分子进化铺平道路。
蛋白质发生突变常常会导致其稳定性发生变化。作为科学家，我们通常很关注这些变化，因为我们想要改造蛋白质的稳定性，或者了解自然发生的突变如何影响其稳定性。进化也关注突变稳定性的变化，因为一个基本的进化要求是蛋白质保持足够稳定以执行其生物学功能。我们的工作基于这样一种想法：应该可以利用进化选择稳定性这一事实，从相关蛋白质中推断特定突变的影响。我们表明，我们确实能够利用蛋白质的进化历史，比基于现有的两种主要策略中的任何一种的方法更准确地通过计算预测先前测量的突变稳定性变化。然后我们测试是否能够预测增加血凝素稳定性的突变，血凝素是一种流感蛋白质，其快速进化是该病毒能够引起年度流行的部分原因。我们通过实验构建携带预测的稳定突变的病毒，并发现其中一些确实提高了病毒在更高温度下生长的能力。因此，我们的计算方法可能有助于理解这种具有医学重要性的病毒的进化。
One selection pressure shaping sequence evolution is the requirement that a protein fold with sufficient stability to perform its biological functions. We present a conceptual framework that explains how this requirement causes the probability that a particular amino acid mutation is fixed during evolution to depend on its effect on protein stability. We mathematically formalize this framework to develop a Bayesian approach for inferring the stability effects of individual mutations from homologous protein sequences of known phylogeny. This approach is able to predict published experimentally measured mutational stability effects (ΔΔG values) with an accuracy that exceeds both a state-of-the-art physicochemical modeling program and the sequence-based consensus approach. As a further test, we use our phylogenetic inference approach to predict stabilizing mutations to influenza hemagglutinin. We introduce these mutations into a temperature-sensitive influenza virus with a defect in its hemagglutinin gene and experimentally demonstrate that some of the mutations allow the virus to grow at higher temperatures. Our work therefore describes a powerful new approach for predicting stabilizing mutations that can be successfully applied even to large, complex proteins such as hemagglutinin. This approach also makes a mathematical link between phylogenetics and experimentally measurable protein properties, potentially paving the way for more accurate analyses of molecular evolution. Mutating a protein frequently causes a change in its stability. As scientists, we often care about these changes because we would like to engineer a protein's stability or understand how its stability is impacted by a naturally occurring mutation. Evolution also cares about mutational stability changes, because a basic evolutionary requirement is that proteins remain sufficiently stable to perform their biological functions. Our work is based on the idea that it should be possible to use the fact that evolution selects for stability to infer from related proteins the effects of specific mutations. We show that we can indeed use protein evolutionary histories to computationally predict previously measured mutational stability changes more accurately than methods based on either of the two main existing strategies. We then test whether we can predict mutations that increase the stability of hemagglutinin, an influenza protein whose rapid evolution is partly responsible for the ability of this virus to cause yearly epidemics. We experimentally create viruses carrying predicted stabilizing mutations and find that several do in fact improve the virus's ability to grow at higher temperatures. Our computational approach may therefore be of use in understanding the evolution of this medically important virus.
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影响因子：
3.4
作者：
Bastolla U;Porto M;Roman HE;Vendruscolo M
通讯作者：
Vendruscolo M
影响因子：
14.9
作者：
Bairoch, Amos;Bougueleret, Lydie;Zhang, Jian
通讯作者：
Zhang, Jian
影响因子：
2.4
作者：
Amin, N;Liu, AD;Schellenberger, V
通讯作者：
Schellenberger, V
DOI：
10.1073/pnas.0406744102
发表时间：
2005-01-18
影响因子：
11.1
作者：
Bloom, JD;Silberg, JJ;Arnold, FH
通讯作者：
Arnold, FH
影响因子：
4.8
作者：
Akasako, A;Haruki, M;Kanaya, S
通讯作者：
Kanaya, S