New Methods for Large-scale Computer Simulation

大规模计算机模拟的新方法

• 批准号: 9497390
• 负责人: JIANPENG MA
• 金额: $ 33.68万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9497390
• 关键词: Advanced Development; Algorithms; CNTNAP1 gene; Communities; Computational Biology; Computer Hardware; Computer Simulation; Cryoelectron Microscopy; Data; Development; Event; Exhibits; Foundations; Goals; Grain; Homology Modeling; Methods; Modeling; Modernization; Molecular; Molecular Conformation; Pathway interactions; Performance; Phase; Plant Roots; Proteins; Research; Role; Sampling; Scheme; Solid; Solvents; Structure; System; Temperature; Testing; X ray diffraction analysis; X-Ray Crystallography; base; blind; computerized tools; computing resources; design; disorder prevention; improved; model building; molecular dynamics; mutant; novel; prevent; protein folding; protein structure; restraint; simulation; structural biology; success; supercomputer; three dimensional structure; tool

Project Summary To predict the three-dimensional structures of a protein solely from its primary sequence remains a grand and elusive challenge in modern computational biology. Molecular dynamics simulation has a high promise for predicting protein structures and folding pathways at molecular details. Recent advances in im- proved computer hardware and enhanced sampling methods have made it possible to ab initio fold proteins of larger size. The highlight of the improved computer hardware is Anton, a massively parallel special-purpose supercomputer designed by D.E. Shaw Research. Anton successfully folded the D14A fast-folding mutant of the 80-residue l-repressor, which was achieved at 49 microseconds (μs) in 643μs-long simulations. On the other hand, the latest advance in enhanced sampling methods is represented by the single-copy continuous simulated tempering (CST) method developed by the PI’s group. The group of Dr. Klaus Schulten incorpo- rated the CST method into the NAMD package, which repeatedly folded the 80-residue l-repressor HG mutant from a fully extended conformation to the native state at 0.5 and 4μs in 10μs-long simulations with Ca root- mean-square deviations (Ca-RMSD) of 1.7 Å on a conventional computing platform. In marked contrast, a complete folding of the same protein was NOT observed using Anton at multiple temperatures even in 100μs- long simulations. This performance of CST in folding simulation has never been matched by any other sam- pling method for similar purposes on conventional computing platforms. Most recently, to further enhance sampling efficiencies in studying larger systems, the PI has developed a more powerful parallel CST (PCST) method. Initial ab initio folding simulation of trp-cage clearly demonstrated that the efficiency of PCST in facili- tating multiple folding and unfolding events was even drastically superior to that of CST. The PCST method serves as a solid foundation for the proposed research in three Specific Aims: 1). Development of the PCST method for enhanced sampling; 2). Design of advanced temperature-dependent restraint schemes for targeted sampling; 3). Development of advanced blind model selection methods for efficient target se- lection. Our in-depth preliminary studies demonstrate that these new methods clearly outperformed all exist- ing methods and suggest a high promise of success for the proposed research. Ultimately, these powerful new algorithms will provide urgently-needed tools for protein simulations, and offer an effective solution for structural refinement in experimental X-ray crystallography and electron cryo-microscopy.

项目概要 仅从蛋白质的一级序列预测蛋白质的三维结构仍然是一个难题 分子动力学模拟在现代计算生物学中具有重大而难以捉摸的挑战。 有望在分子细节上预测蛋白质结构和折叠途径。 经证明的计算机硬件和增强的采样方法使得从头开始折叠蛋白质成为可能 改进后的计算机硬件的亮点是大规模并行专用的Anton。 D.E. Shaw Research 设计的超级计算机成功折叠了 D14A 快速折叠突变体。 80 个残基的 L 阻遏物，在 643μs 长的模拟中以 49 微秒 (μs) 的速度实现。 另一方面，增强采样方法的最新进展以单拷贝连续采样为代表。 由 PI 的 Klaus Schulten 博士小组开发的模拟回火 (CST) 方法。 将 CST 方法纳入 NAMD 包中，该包重复折叠 80 个残基的 L 阻遏物 HG 突变体 在 10μs 长的 Ca 根模拟中，在 0.5 和 4μs 内从完全伸展的构象到天然状态 与传统计算平台相比，均方偏差 (Ca-RMSD) 为 1.7 Å。 即使在 100μs 内，使用 Anton 在多个温度下也未观察到相同蛋白质的完全折叠- CST 在折叠模拟方面的这种性能是任何其他同类产品都无法比拟的。 最近，在传统计算平台上用于类似目的的 pling 方法进一步增强。 为了提高研究大型系统的采样效率，PI 开发了更强大的并行 CST (PCST) trp-cage 的初始从头开始折叠模拟清楚地证明了 PCST 的效率。 多次折叠和展开事件的结果甚至明显优于 PCST 方法。 为拟议的三个具体目标的研究奠定了坚实的基础：1）。 增强采样方法；2）。 有针对性的抽样；3）开发先进的盲模型选择方法，以实现有效的目标选择。 我们深入的初步研究表明，这些新方法明显优于所有现有方法。 最终，这些强大的方法对所提出的研究的成功提出了很高的希望。 新算法将为蛋白质模拟提供急需的工具，并为蛋白质模拟提供有效的解决方案 实验X射线晶体学和电子冷冻显微镜中的结构细化。