MOLECULAR DYNAMICS STUDY OF HIV-1 RNA DIMERIZATION

HIV-1 RNA 二聚化的分子动力学研究

• 批准号: 7723382
• 负责人: Aaron Terrence Frank
• 金额: $ 0.05万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7723382
• 关键词: 5' Untranslated Regions; Adenine; Agreement; Arts; Complex; Computer Retrieval of Information on Scientific Projects Database; Data; Dimerization; Event; Funding; Genome; Genomics; Goals; Grant; HIV; Helix (Snails); Institution; Life Cycle Stages; Methods; Modeling; Molecular Conformation; Names; Pharmaceutical Preparations; Play; Process; RNA; Research; Research Personnel; Resources; Retroviridae; Role; Site; Solvents; Source; Spectrum Analysis; United States National Institutes of Health; Virus; Writing; design; ear helix; interest; melting; molecular dynamics; research study; simulation; tool

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Dimerization of genomic RNA as exemplified by HIV has been shown to be an important event in the life cycle of retroviruses. Studies have indicated that interfering with this dimerization process impairs the ability of the virus to replicate. Therefore much interest exist in understanding the mechanism with the goal of designing anti-dimerization drugs that will ultimately interfere with replication. Dimerization is initiated in the 5'UTR end of the HIV genome. This site is aptly named the dimerization initiation site (DIS). Dimerization involves two steps: first, two DISs from separate copies of the genome associate via their loop regions to form what is known as a loop-loop kissing complex (KC). Second, the kissing complex is then converted to an extended duplex (ED), (see Figure 1). Two distinct models have been proposed to describe the KC => ED conversion. The first involve melting of the helices in both DIS followed by re-annealing to the strand of the other DIS to form the ED. The second involves the cleavage and then religation in the loop-loop region. Up to this point, most of the mechanistic studies that have been carried out have utilized one form of spectroscopy or another. They have revealed that conformational dynamics of the KC plays a key role in the conversion process. However, these methods all suffer from an inherent weakness in that they cannot give us exact atomistic details about the mechanism. Hence MD simulations can prove to be a valuable tool in this regard. As of the writing of this proposal, only a handful of simulations have been carried out on KC and ED. Clearly there is a need to carry out state of the art MD simulations of this dimerization. To determine the mechanism for the KC => ED conversion Biased Molecular Dynamics (BMD) will be used to derive an initial guess to the path between the two conformations, and then Conjugate Peak Refinement (CPR) will be utilized to determine the minimum energy path (MEP) for the conformational change. In agreement with available experiment data, preliminary data from implicit solvent simulations suggest that adenines in the loop-loop region of the KC play an important role in the occurrence of this change. There is now a need to carry out expensive MD simulations utilizing explicit solvent to further and more accurately characterized this KC => ED conversion.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 以HIV为例的基因组RNA的二聚化已被证明是逆转录病毒生命周期中的重要事件。研究表明，干扰这种二聚化过程会损害病毒的复制能力。因此，人们对理解这种机制很感兴趣，目的是设计最终干扰复制的抗二聚化药物。二聚化起始于HIV基因组的5 'UTR末端。该位点被恰当地命名为二聚化起始位点（DIS）。二聚化涉及两个步骤：首先，来自基因组的不同拷贝的两个DIS通过它们的环区域结合，形成所谓的环-环接吻复合物（KC）。其次，接吻复合物然后转化为延伸双链体（艾德）（见图1）。已经提出了两种不同的模型来描述KC =>艾德转换。第一个涉及在两个DIS中的螺旋的解链，然后再退火到另一个DIS的链以形成ED。第二个涉及切割，然后在环-环区域中重新连接。到目前为止，大多数已经进行的机理研究都使用了一种或另一种形式的光谱学。他们揭示了KC的构象动力学在转化过程中起着关键作用。然而，这些方法都有一个固有的弱点，即它们不能给我们关于该机制的确切的原子细节。因此，MD模拟可以证明是一个有价值的工具，在这方面。在撰写本提案时，仅对KC和ED进行了少数模拟。显然，需要对这种二聚进行最先进的MD模拟。为了确定KC =>艾德转化的机制，将使用偏置分子动力学（BMD）来推导两种构象之间的路径的初始猜测，然后使用共轭峰细化（CPR）来确定构象变化的最小能量路径（MEP）。与现有的实验数据一致，隐式溶剂模拟的初步数据表明，腺嘌呤在KC的环-环区域中发挥了重要作用，在发生这种变化。现在需要利用显式溶剂进行昂贵的MD模拟，以进一步和更准确地表征这种KC =>艾德转化。