Equilibrium conformational dynamics in an RNA tetraloop from massively parallel molecular dynamics.
Equilibrium conformational dynamics in an RNA tetraloop from massively parallel molecular dynamics.
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DOI：
10.1093/nar/gkq134
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发表时间：
2010-08
影响因子：
14.9
通讯作者：
Sorin EJ
中科院分区：
文献类型：
--
作者：
DePaul AJ;Thompson EJ;Patel SS;Haldeman K;Sorin EJ
在系综水平上模拟了普遍存在的GNRA四环基序内的构象平衡，包括10 000个独立的全原子分子动力学轨迹，总计超过110 µs的模拟时间。这种强大的采样揭示了一个高度动态的结构，由15个构象微观状态。我们组装一个马尔可夫模型，包括从纳秒到微秒的时间尺度的过渡，并占主导地位的六个关键环构象，有助于周围的原生状态的波动。蛋白质数据库的挖掘提供了丰富的结构，其中GNRA四环参与三级接触形成。在实验数据中最主要观察到的是相邻螺旋区域的小沟内的天然环结构的相互作用。此外，观察到的第二个趋势，其中的tetraloop假设非天然的构象，同时参与多个三级接触，在某些情况下，涉及多个可能的环构象。这种四环柔性可以用于抵消与在形成三级接触时采用非天然环结构相关联的能量损失。因此，GNRA基序不仅容易参与涉及天然环结构的简单三级相互作用，而且还容易适应四环二级构象，以参与更大，更复杂的三级相互作用。
Conformational equilibrium within the ubiquitous GNRA tetraloop motif was simulated at the ensemble level, including 10 000 independent all-atom molecular dynamics trajectories totaling over 110 µs of simulation time. This robust sampling reveals a highly dynamic structure comprised of 15 conformational microstates. We assemble a Markov model that includes transitions ranging from the nanosecond to microsecond timescales and is dominated by six key loop conformations that contribute to fluctuations around the native state. Mining of the Protein Data Bank provides an abundance of structures in which GNRA tetraloops participate in tertiary contact formation. Most predominantly observed in the experimental data are interactions of the native loop structure within the minor groove of adjacent helical regions. Additionally, a second trend is observed in which the tetraloop assumes non-native conformations while participating in multiple tertiary contacts, in some cases involving multiple possible loop conformations. This tetraloop flexibility can act to counterbalance the energetic penalty associated with assuming non-native loop structures in forming tertiary contacts. The GNRA motif has thus evolved not only to readily participate in simple tertiary interactions involving native loop structure, but also to easily adapt tetraloop secondary conformation in order to participate in larger, more complex tertiary interactions.
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