Molecular dynamics simulations identify time scale of conformational changes responsible for conformational selection in molecular recognition of HIV-1 transactivation responsive RNA.
Molecular dynamics simulations identify time scale of conformational changes responsible for conformational selection in molecular recognition of HIV-1 transactivation responsive RNA.
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DOI：
10.1021/ja507812v
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发表时间：
2014-11-05
影响因子：
15
通讯作者：
Carloni P
中科院分区：
文献类型：
--
作者：
Musiani F;Rossetti G;Capece L;Gerger TM;Micheletti C;Varani G;Carloni P
HIV-1达特蛋白和几种小分子通过选择稀疏分布但预先存在的构象与HIV-1反式激活应答RNA（TAR）结合。因此，TAR构象集合和动力学的完整表征对于理解这种范式系统是至关重要的，并且可以促进靶向这种基本调控元件的新抗病毒药物的发现。我们在这里表明，分子动力学模拟可以有效地用于实现这一目标，通过弥合功能相关的时间尺度，目前的实验技术无法访问之间的差距。具体来说，我们已经进行了几个独立的微秒长的分子模拟TAR的基础上最先进的力场之一，RNA，parmbsc 0琥珀。我们的模拟首先验证现有的实验数据，产生一个很好的协议与测得的残余偶极耦合和序参数S2。这与先前的MD模拟（Salmon等人，J. Am. 2013 135，5457-5466），其只能实现与实验RDC值的适度雅阁。接下来，我们将计算引向表征TAR在微秒时间尺度上的内部动态。我们发现，在这个以前难以捉摸的时间尺度上观察到的构象波动有很强的功能导向的字符，因为它们是启动，以维持和协助配体结合。
The HIV-1 Tat protein and several small molecules bind to HIV-1 Trans-Activation Responsive RNA (TAR) by selecting sparsely populated but pre-existing conformations. Thus, a complete characterization of TAR conformational ensemble and dynamics is crucial to understand this paradigmatic system and could facilitate the discovery of new anti-virals targeting this essential regulatory element. We show here that molecular dynamics simulations can be effectively used towards this goal by bridging the gap between functionally-relevant timescales that are inaccessible to current experimental techniques. Specifically, we have performed several independent microsecond long molecular simulations of TAR based on one of the most advanced force fields available for RNA, the parmbsc0 AMBER. Our simulations are first validated against available experimental data, yielding an excellent agreement with measured residual dipolar couplings and order parameter S2. This contrast with previous MD simulations (Salmon et al., J. Am. Chem. Soc. 2013 135, 5457–5466) based on the CHARMM36 force field, which could achieve only modest accord with the experimental RDC values. Next, we direct the computation towards characterizing the internal dynamics of TAR over the microsecond timescale. We show that the conformational fluctuations observed over this previously-elusive timescale have a strong functionally-oriented character in that they are primed to sustain and assist ligand binding.
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影响因子：
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作者：
Du, ZH;Lind, KE;James, TL
通讯作者：
James, TL
影响因子：
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作者：
Frankel, Alan D.
通讯作者：
Frankel, Alan D.
影响因子：
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作者：
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通讯作者：
Varani, Gabriele
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作者：
CALNAN, BJ;TIDOR, B;FRANKEL, AD
通讯作者：
FRANKEL, AD
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作者：
ESSMANN, U;PERERA, L;PEDERSEN, LG
通讯作者：
PEDERSEN, LG