Binding-induced functional-domain motions in the Argonaute characterized by adaptive advanced sampling.
Binding-induced functional-domain motions in the Argonaute characterized by adaptive advanced sampling.
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DOI：
10.1371/journal.pcbi.1009625
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发表时间：
2021-11
影响因子：
4.3
通讯作者：
Zacharias M
中科院分区：
文献类型：
--
作者：
Pourjafar-Dehkordi D;Zacharias M
与短的microRNA（miRNA）结合使用的蛋白质可以靶向抑制或降解的mRNA分子，并在许多调节过程中起关键作用。我的重要性。对于热嗜热（Ttago）系统指南（二进制）和指导/目标结合（三元）络合物，但我们仍未了解Apo和目标态度的指导/目标模拟方法（Hamilton to Ackel），而不是hamilto to ackel（hamilto and ackel）（hamilto and ackel）（hamilto and ackel），指导和目标中介域运动的结合是如何理解的。 H-REMD技术表明，与常规的MD模拟相比，APO中的域排列以及二进制和三元复合物的取样，与APO状态域的排列相比，与更紧凑的状态（封闭式）状态相比，主要是在指导/目标绑定中进行域中的较大范围的范围。在指南和目标链之间形成15或16个基碱对的三元络合物（而不是14个）的比较模拟，导致3'Guide链与PAZ域和域重排的相结合。
翻译后的基因沉默是一个重要的过程，是在真核生物和原核生物中调节蛋白质的合成，作为RNA诱导的 - 沉默 - 复合物（RISC）的一部分。完整的目标mRNA。靶标mRNA的激活和特定的裂解涉及完全理解的域重排，我们将高级分子动力学采样技术应用于特定的加速度加速域的动力。指导和目标结合所需的开放动作也提供了解释，为什么在指导和目标链之间至少要有15或16个基础对。
Argonaute proteins in combination with short microRNA (miRNAs) can target mRNA molecules for translation inhibition or degradation and play a key role in many regulatory processes. The miRNAs act as guide RNAs that associate with Argonaute and the complementary mRNA target region. The complex formation results in activation of Argonaute and specific cleavage of the target mRNA. Both the binding and activation processes involve essential domain rearrangements of functional importance. For the Thermus Thermophilus Argonaute (TtAgo) system guide-bound (binary) and guide/target-bound (ternary) complexes are known but how the binding of guide and target mediate domain movements is still not understood. We have studied the Argonaute domain motion in apo and guide/target bound states using Molecular Dynamics simulations and a Hamiltonian replica exchange (H-REMD) method that employs a specific biasing potential to accelerate domain motions. The H-REMD technique indicates sampling of a much broader distribution of domain arrangements both in the apo as well as binary and ternary complexes compared to regular MD simulations. In the apo state domain arrangements corresponding to more compact (closed) states are mainly sampled which undergo an opening upon guide and guide/target binding. Whereas only limited overlap in domain geometry between apo and bound states was found, a larger similarity in the domain distribution is observed for the simulations of binary and ternary complexes. Comparative simulations on ternary complexes with 15 or 16 base pairs (bp) formed between guide and target strands (instead of 14) resulted in dissociation of the 3’-guide strand from the PAZ domain and domain rearrangement. This agrees with the experimental observation that guide-target pairing beyond 14 bps is required for activation and gives a mechanistic explanation for the experimentally observed activation process. Post-transcriptional gene silencing is an important process to regulate protein synthesis in eukaryotes and prokaryotes. The Argonaute proteins as part of the RNA-induced-silencing-complex (RISC) form a central element of the process by silencing of a target messenger RNA (mRNA) via degradation or repression of translation. The Argonaute protein binds initially a short RNA that acts as a guide to promote binding of a complementary target mRNA. The complex formation can lead to activation of Argonaute and specific cleavage of the target mRNA. The whole process involves domain rearrangements that are not fully understood. We applied an advanced Molecular Dynamics sampling technique to specifically accelerate domain motions of the Thermus Thermophilus Argonaute (TtAgo) system in apo, guide bound and guide/target bound states. The simulations indicate only limited overlap of domain arrangements in apo and bound states and identified domain opening motions necessary for guide and target binding. The study also offers an explanation why a minimum of 15 or 16 base pairs between guide and target strands are necessary for Argonaute activation.
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