COMPUTATIONAL STUDIES OF RNA RECOGNITION AND CATALYSIS

RNA 识别和催化的计算研究

基本信息

  • 批准号:
    7956307
  • 负责人:
  • 金额:
    $ 0.08万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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. Accurate RNA recognition by other biomolecules such as proteins, cofactors and other RNA molecules are critical to many cellular functions. Employing a variety of computational chemistry tools such as molecular dynamics simulations, quantum calculations and hybrid quantum mechanical/molecular mechanics methods, our research examines three primary areas, messenger RNA - transfer RNA (mRNA-tRNA) recognition, a key step in the translation of proteins, protein-RNA interactions in human immunodeficiency virus (HIV) and pKa calculations in catalytic RNA molecules. In the first area, the role of naturally occurring, posttranscriptionally modified bases in affecting tRNA-mRNA recognition is examined. In human tRNALys,3, we have found that a modified base at position 37 are required for maintenance of a canonical stair-stepped conformation in the anticodon bases (34-36). Ab initio studies employing natural bond orbital analysis with the M05-2X functional are underway to determine the underlying stabilizing forces and the role of modified bases at the 37th position in retaining a stair-stepped conformation in all tRNAs. Optimization of hydrogen positions at the M05-2X/6-31+G(d,p) theory level needs to be carried out for tetranucleotides and trinucleotides (dimers are ~1400 basis functions), which on our local machines can take greater than 45 days/calculation. Faster computing resources are required to make progress on this project. In the second area of research, we are examining the role of water and electrostatics in RNA-peptide recognition. In late phase Rev-RRE recognition mediates nucleocytoplasmic export of partially and unspliced HIV mRNA. From in vitro selection studies performed by Frankel and coworkers, a synthetic peptide known as RSG-1.2 has been found to bind RRE with greater affinity and specificity than the native Rev peptide. We have simulated both Rev and RSG-1.2 peptides complexed with the RRE RNA in explicit water using AMBER and have found a correlation between water structure in the peptide-RNA complexes and binding affinity. More simulations to corroborate earlier findings are required. Systems are roughly 35,000 atoms and data could be collected more efficiently employing parallel AMBER code. Lastly, in collaboration with Darrin York, we are calculating pKas in catalytic RNA molecules known as ribozymes. The thermodynamic integration methods require equilibrated starting systems. Current systems are carried out in explicit solvent (TIP4Pew), include 150 mM NaCl buffer solution beyond the neutralized RNA and are about 75,000 atoms. These systems require a number of simulated annealing rounds to equilibrate the ion atmosphere and then the RNA must be subsequently equilibrated in the presence of the buffer before TI calculations can be performed. This allocation is requested to take advantage of parallel computing facilities while also exploring optimum Teragrid platforms for future allocation requests.
该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金, 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说,它不一定是研究者的机构。 其他生物分子(例如蛋白质、辅因子和其他 RNA 分子)对 RNA 的准确识别对于许多细胞功能至关重要。我们的研究采用分子动力学模拟、量子计算和混合量子力学/分子力学方法等多种计算化学工具,研究了三个主要领域:信使 RNA - 转移 RNA (mRNA-tRNA) 识别、蛋白质翻译的关键步骤、人类免疫缺陷病毒 (HIV) 中的蛋白质-RNA 相互作用以及催化 RNA 分子中的 pKa 计算。在第一个领域,研究了天然存在的转录后修饰碱基在影响 tRNA-mRNA 识别中的作用。在人类 tRNALys,3 中,我们发现第 37 位的修饰碱基是维持反密码子碱基 (34-36) 中规范阶梯式构象所必需的。采用自然键轨道分析和 M05-2X 功能的从头开始研究正在进行中,以确定潜在的稳定力以及第 37 位修饰碱基在所有 tRNA 中保留阶梯构象中的作用。需要对四核苷酸和三核苷酸(二聚体约为 1400 个基函数)在 M05-2X/6-31+G(d,p) 理论水平上进行氢位置优化,这在我们本地的机器上可能需要超过 45 天/计算。该项目需要更快的计算资源才能取得进展。在第二个研究领域,我们正在研究水和静电在 RNA 肽识别中的作用。在后期,Rev-RRE 识别介导部分和未剪接的 HIV mRNA 的核细胞质输出。 Frankel 及其同事进行的体外选择研究发现,一种名为 RSG-1.2 的合成肽与 RRE 的结合比天然 Rev 肽具有更高的亲和力和特异性。我们使用 AMBER 模拟了在纯水中与 RRE RNA 复合的 Rev 和 RSG-1.2 肽,并发现了肽-RNA 复合物中的水结构与结合亲和力之间的相关性。需要更多的模拟来证实早期的发现。系统大约有 35,000 个原子,使用并行 AMBER 代码可以更有效地收集数据。最后,我们与 Darrin York 合作,计算称为核酶的催化 RNA 分子的 pKa。热力学积分方法需要平衡的启动系统。目前的系统是在显性溶剂 (TIP4Pew) 中进行的,除了中和的 RNA 之外还包括 150 mM NaCl 缓冲溶液,并且大约有 75,000 个原子。这些系统需要多次模拟退火来平衡离子气氛,然后必须在缓冲液存在的情况下平衡 RNA,然后才能进行 TI 计算。请求这种分配是为了利用并行计算设施,同时还为未来的分配请求探索最佳的 Teragrid 平台。

项目成果

期刊论文数量(0)
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Maria Colleen Nagan其他文献

Maria Colleen Nagan的其他文献

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{{ truncateString('Maria Colleen Nagan', 18)}}的其他基金

COMPUTATIONAL STUDIES OF RNA RECOGNITION AND CATALYSIS
RNA 识别和催化的计算研究
  • 批准号:
    8364199
  • 财政年份:
    2011
  • 资助金额:
    $ 0.08万
  • 项目类别:
COMPUTATIONAL STUDIES OF RNA RECOGNITION AND CATALYSIS
RNA 识别和催化的计算研究
  • 批准号:
    8171777
  • 财政年份:
    2010
  • 资助金额:
    $ 0.08万
  • 项目类别:
MOLECULAR DYNAMICS STUDIES OF RIBONUCLEIC ACID STRUCTURE AND FUNCTION: HIV MRNA
核糖核酸结构和功能的分子动力学研究:HIV mRNA
  • 批准号:
    7723223
  • 财政年份:
    2008
  • 资助金额:
    $ 0.08万
  • 项目类别:
MOLECULAR DYNAMICS STUDIES OF RIBONUCLEIC ACID STRUCTURE AND FUNCTION
核糖核酸结构和功能的分子动力学研究
  • 批准号:
    7601486
  • 财政年份:
    2007
  • 资助金额:
    $ 0.08万
  • 项目类别:

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