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首页> 外文期刊>ACS Omega >Principles of tRNAAla Selection by Alanyl–tRNA Synthetase Based on the Critical G3·U70 Base Pair
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Principles of tRNAAla Selection by Alanyl–tRNA Synthetase Based on the Critical G3·U70 Base Pair

机译：基于关键G3·U70碱基对的丙氨酰–tRNA合成酶选择tRNAAla的原理

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Throughout evolution, the presence of a single G3·U70 mismatch in the acceptor stem of tRNAAla is the major determinant for aminoacylation with alanine by alanyl–tRNA synthetase (AlaRS). Recently reported crystal structures of the complexes AlaRS–tRNAAla/G3·U70 and AlaRS–tRNAAla/A3·U70 suggest two very different conformations, representing a reactive and a nonreactive state, respectively. On the basis of these structures, it has been proposed that the G3·U70 base pair guides the ?CCA end of the tRNA acceptor stem into the active site of AlaRS, thereby enabling aminoacylation. The crystal structures open up the possibility of directly computing the energetics of tRNA specificity by AlaRS. We have carried out molecular dynamics free-energy simulations to quantitatively estimate tRNA discrimination by AlaRS, focusing on the mutations of the single critical base pair G3·U70 to uncover the energetics underlying the accuracy of tRNA selection. The calculations show that the reactive complex is highly selective in favor of the cognate tRNAAla/G3·U70 over its noncognate analogues (A3·U70/G3·C70/A3·C70). In contrast, the nonreactive complex is predicted to be unselective between tRNAAla/G3·U70 and tRNAAla/A3·U70. Utilizing our calculated relative binding free energies, we show how a simple three-step kinetic scheme for aminoacylation, involving both an initial nonspecific binding step and a subsequent transition to a selective reactive complex, accounts for the observed kinetics of the process.
机译：在整个进化过程中，tRNAAla受体茎中单个G3·U70错配的存在是丙氨酰tRNA合成酶（AlaRS）与丙氨酸进行氨酰化的主要决定因素。最近报道的复合物AlaRS–tRNAAla / G3·U70和AlaRS–tRNAAla / A3·U70的晶体结构表明两个非常不同的构象，分别代表反应态和非反应态。基于这些结构，已经提出，G3·U70碱基对将tRNA受体茎的βCCA末端引导至AlaRS的活性位点，从而实现氨基酰化。晶体结构打开了通过AlaRS直接计算tRNA特异性能量的可能性。我们已经进行了分子动力学自由能模拟，通过AlaRS定量评估tRNA的分辨力，重点是单个关键碱基对G3·U70的突变，以揭示tRNA选择准确性背后的能量学。计算表明，与非同源类似物（A3·U70 / G3·C70 / A3·C70）相比，反应性络合物对同源tRNAAla / G3·U70具有更高的选择性。相反，预计非反应性复合物在tRNAAla / G3·U70和tRNAAla / A3·U70之间是非选择性的。利用我们计算出的相对结合自由能，我们展示了一个简单的三步氨基酰化动力学方案，包括初始的非特异性结合步骤和随后的向选择性反应性复合物的过渡，如何解释了该过程中观察到的动力学。

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