Computation of conformational coupling in allosteric proteins.
Computation of conformational coupling in allosteric proteins.
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DOI：
10.1371/journal.pcbi.1000484
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发表时间：
2009-08
影响因子：
4.3
通讯作者：
Thomas WE
中科院分区：
文献类型：
--
作者：
Kidd BA;Baker D;Thomas WE
在变构调节中，在一个位点结合蛋白质的效应分子诱导构象变化，其改变远端活性位点的结构和功能。变构的计算建模中的两个关键挑战是从另一种变构状态的结构开始预测一种变构状态的结构，并阐明效应位点和活性位点的构象耦合的机制。在这里，我们使用Rosetta高分辨率结构预测方法来解决这两个挑战。我们发现，该方法可以概括为相应的无配体状态的单域变构蛋白的效应器结合形式的松弛，特别是当采样集中在已知的构象变化最显着的区域。在两个变构状态之间和周围的景观中散布的大型构象集合中的接触对残基之间的耦合的分析表明，过渡是从更松散地彼此耦合的紧密耦合的相互作用的残基组的块建立的。生物调节的一种常见手段是变构，其中效应分子结合蛋白质上的一个位点并诱导构象变化，从而改变远端活性位点的活性。通常高分辨率结构被确定为一种状态的变构蛋白质，而不是其他。为了探测这种情况下的变构构象变化，我们描述了一种计算方法，用于预测一种蛋白质的变构状态的结构，从另一种蛋白质的知识开始。我们的方法还提供了一个详细的地图的自由能景观穿越变构过渡，并揭示了相互作用的残基对之间的耦合，过渡的基础。
In allosteric regulation, an effector molecule binding a protein at one site induces conformational changes, which alter structure and function at a distant active site. Two key challenges in the computational modeling of allostery are the prediction of the structure of one allosteric state starting from the structure of the other, and elucidating the mechanisms underlying the conformational coupling of the effector and active sites. Here we approach these two challenges using the Rosetta high-resolution structure prediction methodology. We find that the method can recapitulate the relaxation of effector-bound forms of single domain allosteric proteins into the corresponding ligand-free states, particularly when sampling is focused on regions known to change conformation most significantly. Analysis of the coupling between contacting pairs of residues in large ensembles of conformations spread throughout the landscape between and around the two allosteric states suggests that the transitions are built up from blocks of tightly coupled interacting sets of residues that are more loosely coupled to one another. A common means of biological regulation is allostery, in which an effector molecule binds to one site on a protein and induces a conformational change which changes activity at a distant active site. Frequently high resolution structures are determined for one state of an allosteric protein but not the other. To probe the allosteric conformational changes in such cases, we describe a computational method for predicting the structure of one allosteric state of a protein starting with knowledge of another. Our method also provides a detailed map of the free energy landscape traversed in an allosteric transition and reveals the coupling between interacting residue pairs that underlies the transition.
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影响因子：
2.9
作者：
Daily, Michael D.;Upadhyaya, Tarak J.;Gray, Jeffrey J.
通讯作者：
Gray, Jeffrey J.
影响因子：
5.6
作者：
Bellsolell, L;Cronet, P;Coll, M
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Coll, M
DOI：
10.1073/pnas.95.17.9903
发表时间：
1998-08-18
影响因子：
11.1
作者：
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通讯作者：
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影响因子：
2.9
作者：
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通讯作者：
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影响因子：
5.6
作者：
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通讯作者：
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