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: 7956241
• 负责人: Aaron Terrence Frank
• 金额: $ 0.08万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7956241
• 关键词: 5' Untranslated Regions; Adenine; Agreement; Arts; Biomedical Research; Complex; Computer Retrieval of Information on Scientific Projects Database; Data; Dimerization; Event; Funding; Genome; Genomics; Goals; Grant; HIV; HIV-1; High Performance Computing; 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; 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利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 以HIV为代表的基因组RNA二聚化已被证明是逆转录病毒生命周期中的一个重要事件。研究表明，干扰这种二聚化过程会削弱病毒的复制能力。因此，人们对了解这一机制非常感兴趣，目的是设计最终干扰复制的抗二聚化药物。二聚化在HIV基因组的5‘非编码区末端启动。这个位置被恰当地命名为二聚起始点(DIS)。二聚化包括两个步骤：首先，来自不同基因组拷贝的两个DISs通过它们的环区联系在一起，形成所谓的环环亲吻复合体(KC)。其次，接吻复合体随后被转换为扩展双工(ED)(参见图1)。已经提出了两种不同的模型来描述KC=&gt；ED转换。第一个过程涉及两个DIS中螺旋的熔化，然后重新加热到另一个DIS的链上形成ED。第二个阶段涉及到环环区的卵裂和宗教活动。到目前为止，大多数已经开展的机制研究都利用了这样或那样的光谱学形式。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，即它们不能给我们提供关于机制的确切原子细节。因此，分子动力学模拟在这方面可以被证明是一个有价值的工具。截至撰写本提案时，仅对KC和ED进行了少数几次模拟。显然，需要对这种二聚化进行最先进的MD模拟。为了确定KC=&gt；ED转换的机制，将使用偏向分子动力学(BMD)来推导出两种构象之间的路径的初始猜测，然后将使用共轭峰精化(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，来自隐式溶剂模拟的初步数据表明，KC环环区域的腺嘌呤在这种变化的发生中发挥了重要作用。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=ED转换。