MODELING THE FORCED EXTENSION OF NICKED DNA

模拟带切口 DNA 的强制延伸

• 批准号: 7723366
• 负责人: DAVID BERATAN
• 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/7723366
• 关键词: Amber; Behavior; Benchmarking; Biological Models; Biological Process; Computer Retrieval of Information on Scientific Projects Database; Computer software; DNA; DNA Repair; DNA Sequence; Data; Fostering; Funding; Grant; Institution; Knowledge; Learning; Modeling; Nanotechnology; Oligonucleotides; Research; Research Personnel; Resources; Running; Sampling; Series; Source; Theoretical Studies; United States National Institutes of Health; molecular dynamics; nanosecond; programs; simulation

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. We request Teragrid resources for our theoretical study of the forced extension of nicked DNA chains. Nicked DNA chains, self-assembled from short oligonucleotides, have been recently studied experimentally by one of the co-PIs (Kersey et al., J. Am. Chem. Soc., 126:3038-3039, 2004). The behavior of the nicked chains during the forced extension was found to be remarkably different from that of continuous DNA (cf. Strick et al., Ann. Rev. Bioph. Biomol. Struct., 29:523-543, 2000; Harris et al., Bioph. J., 88:1684-1691, 2004). We seek to uncover the structural mechanism of the nicked DNA forced extension and, perhaps, learn the ways to program different extension regimes by manipulating the DNA sequence. The obtained knowledge may foster nanotechnology applications of nicked DNA chains and advance our understanding of key biological processes, such as DNA repair and replication. The extension of nicked DNA is modeled in a series of steered molecular dynamics (SMD) simulations (Isralewitz et. al, Curr. Opin. Struct. Biol. 11:224-230, 2001), using the classical MD software NAMD and AMBER. The model system consists of around 45 thousand atoms. The preliminary studies reveal several possible scenarios of structural changes of nicked DNA during the forced extension. Additional computational resources are needed to collect a sufficient statistical sampling of these scenarios, probe different extension velocities, and study different sequences of nicked DNA. We request 30,000 SUs on Teragrid machines. Using NAMD benchmarks (http://www.ks.uiuc.edu/Research/namd/performance.html), we estimate that our typical SMD simulation of 10-20 nanoseconds (ns) requires about 4,000-8,000 SUs when run on 16 to 64 CPUs of Cray XT3; only 1,000-2,000 SUs would be required on a faster BlueGene/L machine. Therefore, our request amounts to 5-8 additional SMD runs on slower Teragrid machines, allowing us to approximately double our presently accumulated data sampling at the probed extension velocities. On faster Teragrid machines, the allocation would be equivalent to 20-30 SMD runs, which would enable us to also probe another DNA sequence and repeat the original simulations with a different forcefield. In case of encouraging results, a more extended proposal for continuing the studies will be submitted to MRAC.

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。 我们请求 Teragrid 资源来进行带切口 DNA 链强制延伸的理论研究。最近，其中一位 co-PI 对由短寡核苷酸自组装而成的带切口 DNA 链进行了实验研究（Kersey 等人，J. Am. Chem. Soc.，126：3038-3039，2004）。发现强制延伸过程中带切口的链的行为与连续 DNA 的行为显着不同（参见 Strick 等人，Ann.Rev.Bioph.Biomol.Struct.，29：523-543，2000；Harris 等人，Bioph.J.，88：1684-1691，2004）。我们试图揭示带切口的 DNA 强制延伸的结构机制，或许还可以了解通过操纵 DNA 序列来编程不同延伸机制的方法。所获得的知识可能会促进带切口 DNA 链的纳米技术应用，并增进我们对 DNA 修复和复制等关键生物过程的理解。使用经典 MD 软件 NAMD 和 AMBER，在一系列引导分子动力学 (SMD) 模拟中对带切口 DNA 的延伸进行建模（Isralewitz 等人，Curr. Opin. Struct. Biol. 11:224-230, 2001）。该模型系统由大约 45,000 个原子组成。初步研究揭示了带切口 DNA 在强制延伸过程中结构变化的几种可能情况。需要额外的计算资源来收集这些场景的足够统计样本、探测不同的延伸速度并研究不同的切口 DNA 序列。我们在 Teragrid 机器上请求 30,000 个 SU。使用 NAMD 基准测试 (http://www.ks.uiuc.edu/Research/namd/performance.html)，我们估计，当在 16 至 64 个 Cray XT3 CPU 上运行时，我们的 10-20 纳秒 (ns) 典型 SMD 模拟需要大约 4,000-8,000 个 SU；更快的 BlueGene/L 机器只需要 1,000-2,000 个 SU。因此，我们的请求相当于在速度较慢的 Teragrid 机器上额外运行 5-8 个 SMD，从而使我们能够以探测的扩展速度将目前积累的数据采样大约增加一倍。在更快的 Teragrid 机器上，分配相当于 20-30 SMD 运行，这将使我们能够探测另一个 DNA 序列并使用不同的力场重复原始模拟。如果结果令人鼓舞，将向 MRAC 提交一份更广泛的继续研究提案。