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Conformational Dynamics of thiM Riboswitch To Understand the Gene Regulation Mechanism Using Markov State Modeling and the Residual Fluctuation Network Approach
Journal of Chemical Information and Modeling ( IF 5.6 ) Pub Date : 2018-06-25 00:00:00 , DOI: 10.1021/acs.jcim.8b00155
Manish Kesherwani 1 , Kutumbarao N. H. V 1 , Devadasan Velmurugan 1
Affiliation  

Thiamine pyrophosphate (TPP) riboswitch is a cis-regulatory element in the noncoding region of mRNA. The aptamer domain of TPP riboswitch detects the high abundance of coenzyme thiamine pyrophosphate (TPP) and modulates the gene expression for thiamine synthetic gene. The mechanistic understanding in recognition of TPP in aptamer domain and ligand-induced compactness for folding of expression platform are most important to designing novel modulators. To understand the dynamic behavior of TPP riboswitch upon TPP binding, molecular dynamics simulations were performed for 400 ns in both apo and TPP bound forms of thiM riboswitch from E. coli and analyzed in terms of eRMSD-based Markov state modeling and residual fluctuation network. Markov state models show good correlations in transition probability among metastable states from simulated trajectory and generated models. Structural compactness in TPP bound form is observed which is correlated with SAXS experiment. The importance of junction of P4 and P5 is evident during dynamics, which correlates with FRET analysis. The dynamic nature of two sensor forearms is due to the flexible P1 helix, which is its intrinsic property. The transient state in TPP-bound form was observed in the Markov state model, along with stable states. We believe that this transient state is responsible to assist the influx and outflux of ligand molecule by creating a solvent channel around the junction region of P4 and P5 and such a structure was anticipated in FRET analysis. The dynamic nature of riboswitch is dependent on the interaction between residues on distal loops L3 and L5/P3 and junction P4 and P5, J3/2 which stabilize the J2/4. It helps in the transfer of allosteric information between J2/4 and P3/L5 tertiary docking region through the active site residues. Understanding such information flow will benefit in highlighting crucial residues in highly dynamic and kinetic systems. Here, we report the residues and segments in riboswitch that play vital roles in providing stability and this can be exploited in designing inhibitors to regulate the functioning of riboswitches.

中文翻译:

ThiM Riboswitch构象动力学通过马尔可夫状态建模和残差波动网络方法了解基因调控机制

硫胺焦磷酸盐(TPP)核糖开关是mRNA非编码区中的顺式调节元件。TPP核糖开关的适体结构域可检测到丰富的辅酶硫胺素焦磷酸(TPP)并调节硫胺素合成基因的基因表达。在适体结构域中识别TPP的机制理解和表达平台折叠的配体诱导的致密性对于设计新型调节剂最为重要。为了了解TPP核糖开关在TPP结合时的动力学行为,在大肠杆菌中以thiM核糖开关的载脂蛋白和TPP结合形式对分子进行了400 ns的分子动力学模拟并根据基于eRMSD的马尔可夫状态建模和残差波动网络进行了分析。马尔可夫状态模型显示出来自模拟轨迹和生成模型的亚稳态之间的跃迁概率具有良好的相关性。观察到TPP结合形式的结构紧密性,这与SAXS实验相关。在动力学过程中,P4和P5连接的重要性很明显,这与FRET分析相关。两个传感器前臂的动态特性是由于其固有的特性而具有灵活的P1螺旋线。在马尔可夫状态模型中观察到TPP结合形式的瞬态以及稳定状态。我们认为,这种瞬态通过在P4和P5的连接区域周围形成溶剂通道来协助配体分子的流入和流出,并且这种结构在FRET分析中是可以预期的。核糖开关的动态性质取决于远端环L3和L5 / P3与连接点P4和P5,J3 / 2上的残基之间的相互作用,该相互作用稳定了J2 / 4。它有助于通过活动位点残基在J2 / 4和P3 / L5三级对接区域之间传递变构信息。了解此类信息流将有助于突出显示高动态和动力学系统中的关键残基。在这里,我们报告了核糖开关中的残基和片段在提供稳定性方面起着至关重要的作用,这可用于设计抑制剂来调节核糖开关的功能。核糖开关的动态性质取决于远端环L3和L5 / P3与连接点P4和P5,J3 / 2上的残基之间的相互作用,该相互作用稳定了J2 / 4。它有助于通过活动位点残基在J2 / 4和P3 / L5三级对接区域之间传递变构信息。了解此类信息流将有助于突出显示高动态和动力学系统中的关键残基。在这里,我们报告了核糖开关中的残基和片段在提供稳定性方面起着至关重要的作用,这可用于设计抑制剂来调节核糖开关的功能。核糖开关的动态性质取决于远端环L3和L5 / P3与连接点P4和P5,J3 / 2上的残基之间的相互作用,该相互作用稳定了J2 / 4。它有助于通过活动位点残基在J2 / 4和P3 / L5三级对接区域之间传递变构信息。了解此类信息流将有助于突出显示高动态和动力学系统中的关键残基。在这里,我们报告了核糖开关中的残基和片段在提供稳定性方面起着至关重要的作用,这可用于设计抑制剂来调节核糖开关的功能。它有助于通过活动位点残基在J2 / 4和P3 / L5三级对接区域之间传递变构信息。了解此类信息流将有助于突出显示高动态和动力学系统中的关键残基。在这里,我们报告了核糖开关中的残基和片段在提供稳定性方面起着至关重要的作用,这可用于设计抑制剂来调节核糖开关的功能。它有助于通过活动位点残基在J2 / 4和P3 / L5三级对接区域之间传递变构信息。了解此类信息流将有助于突出显示高动态和动力学系统中的关键残基。在这里,我们报告了核糖开关中的残基和片段在提供稳定性方面起着至关重要的作用,这可用于设计抑制剂来调节核糖开关的功能。
更新日期:2018-06-25
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