ITR/AP: Tools and Methods for Multiscale Biomolecular Simulations

ITR/AP：多尺度生物分子模拟的工具和方法

• 批准号: 0121361
• 负责人: Celeste Sagui
• 金额: $ 296.22万
• 依托单位: North Carolina State University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-10-01 至 2007-09-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0121361&HistoricalAwards=false
• 关键词: ITR; AP; Tools; Methods; Multiscale

This award is the result of a proposal submitted to the Information Technology Research (ITR) Initiative. The grant is being funded jointly by the Divisions of Materials Research, Chemistry, Biological Infrastructure and Molecular and Cellular Biosciences. Large-scale electronic structure and atomistic simulations have proven themselves to be essential in advancing our understanding of the complex physical and chemical transformations undertaken by biomolecules in carrying out their cellular functions. The breathtaking progress in computer performance and recent advances in algorithms for molecular simulations systems are opening unprecedented opportunities to investigate the biomolecular processes in silico, i.e., by accurate modeling of fundamental natural laws and processes through their computer representations. The overarching goal of this project is to seize this opportunity and develop a set of computational methods and tools which will achieve a qualitatively new level of usefulness, flexibility, accuracy and scientific impact. These goals will be achieved by combining significant new developments of both quantum and classical simulation methods, exploring their interoperabilities, and by the exploitation of parallelism and recent algorithmic advances. Realistic biomolecular simulations are notoriously difficult because they typically involve very large and complex mamcromolecules such as DNA or proteins, which need to be simulated in a proper solvent environment. While ideally one would like to describe biomolecules and all their transformations with ab initio accuracy, this is clearly an unreasonable goal given the computational demands of such simulations. What is, however, well within reach is an integrated multiscale approach that treats different parts of the biomolecular system with differing levels of accuracy, depending on their imporatnce. For instance, in order to understand enzymatic reactions, there is a need to understand the structure and chemistry of the complex reaction centers built up by the three-dimensional folding of proteins as accurately as possible. Our strategy is to decompose the large system into a set of overlapping nested regions, using an appropriate physical representation (quantum, classical, or continuum) and to develop interfaces that provides a physically consistent description and keeps the fundamental physical laws intact.To achieve these goals we aim to develop a set of modular tools for biomolecular simulations which treat parts of the system at a quantum, classical atomistic or continuum level, as needed for efficient studies of large moelcular complexes. At the quantum level, we will treat the system with a combination of quantum Monte Carlo (QMC), quantum chemical post-Hartree-Fock and density functional methods (DFT). At an intermediate level, calssical molecular dynamics with empirical force fields will be used, while continuum methods may serve to describe the large length-scale properties of the solvent environment. In order to build such tools, substantial algorithmic improvements to current methods need to be developed at each "level" of the physical representation, along with proper interfaces between the different descriptions of the system. The most important innovative features of our approach will be the following: (i) the unprecedented use of the highly accurate QMC approach and its new developments for biological simulations; (ii) at a density functional level, algorithmic improvements will enable routine calculations of thousands of atoms including quantum molecular dynamics, and also dynamically call the QMC approach for checking the accuracy of the DFT functionals in problematic cases; (iii) the electrostatic interactions will be treated in a highly accurate manner in the classical mechanics regions, with the implementation of point multipolar expansions, polarizabilities and low-order continuous wavefunctions, which will provide a robust interface between the quantum and classical regions; (iv) the codes will be based on real-space grids as these enable true O(N) scaling on parallel machines, are more flexible in terms of boundary conditions, and allow for additional gains in accuracy, while preserving stability, via the introduction of non-uniform grids; (v) our methodology relies on proven multigrid methods that allow for an accelerated convergence to the proper solution on different length scales; (vi) the codes will be developed under an Open Source GPL license and made available to the public as "add-on" packages to existing codes, such as AMBER; (vii) the codes will be scalable and portable, running on both massively parallel supercomputers and workstations. They will use modern Web-based technologies for providing access to simulations and their results.The new capabilities will enable us to attack key challenges and paradigmatic biomolecular problems, such as enzymatic reactions, blood coagulation proteins, and others, both as a part of our ITR program and through the efforts of the scientific community at large. Ultimately, we will distribute our codes freely to the biosimulation community via the GPL license in order to achieve a wide spread dissemination of results and maximum scientific impact. In addition to the research goals, this program has considerable educational goals, aimed at developing a set of interdisciplinary modern courses that will generate student interest and excitement about computational and simulation science and technology. Toward this end, we will develop a curriculum for the Center for High Performance Supercomputing being currently formed at NCSU, build a set of educational tools which will be introduced and disseminated during summer workshops for students and postdocs.%%%

该奖项是提交给信息技术研究(ITR)倡议的一项提案的结果。这笔赠款由材料研究、化学、生物基础设施以及分子和细胞生物科学部联合资助。大规模的电子结构和原子模拟已被证明是促进我们对生物分子在执行其细胞功能过程中进行的复杂的物理和化学变化的理解所必需的。计算机性能的惊人进步和分子模拟系统算法的最新进展为研究电子计算机中的生物分子过程提供了前所未有的机会，即通过计算机表示对基本自然规律和过程进行精确建模。该项目的总体目标是抓住这一机会，开发一套计算方法和工具，使其在有用性、灵活性、准确性和科学影响方面达到一个全新的水平。这些目标将通过结合量子和经典模拟方法的重大新发展，探索它们的互操作性，以及利用并行性和最新的算法进步来实现。现实的生物分子模拟是出了名的困难，因为它们通常涉及非常大和复杂的大分子，如DNA或蛋白质，需要在适当的溶剂环境中进行模拟。虽然理想情况下，人们希望从从头算起准确地描述生物分子及其所有的转化，但考虑到这种模拟的计算要求，这显然是一个不合理的目标。然而，触手可及的是一种综合的多尺度方法，它以不同的精度处理生物分子系统的不同部分，具体取决于它们的重要性。例如，为了理解酶反应，需要尽可能准确地了解蛋白质三维折叠建立的复杂反应中心的结构和化学。我们的策略是使用适当的物理表示(量子、经典或连续统)将大系统分解成一组重叠的嵌套区域，并开发提供物理上一致的描述并保持基本物理定律完整的界面。为了实现这些目标，我们的目标是开发一套用于生物分子模拟的模块化工具，这些工具在量子、经典原子或连续统水平上处理系统的部分，以有效地研究大分子络合物。在量子水平上，我们将结合量子蒙特卡罗(QMC)、量子化学后Hartree-Fock和密度泛函方法(DFT)来处理该系统。在中级水平上，将使用具有经验力场的物理分子动力学，而连续统方法可能用于描述溶剂环境的大长度尺度性质。为了建立这样的工具，需要在物理表示的每个“级别”上开发对当前方法的实质性算法改进，以及系统的不同描述之间的适当接口。我们的方法最重要的创新特征如下：(I)高精度QMC方法及其在生物模拟中的新发展的前所未有的使用；(Ii)在密度泛函水平上，算法的改进将使包括量子分子动力学在内的数千个原子的常规计算成为可能，并在有问题的情况下动态调用QMC方法来检查DFT泛函的准确性；(Iii)在经典力学领域将以高精度的方式处理静电相互作用，实现点多极展开、极化率和低阶连续波函数，这将在量子和经典区域之间提供可靠的接口；(4)代码将以实空间网格为基础，因为这些网格能够在并行机上实现真正的O(N)缩放，在边界条件方面更加灵活，并允许通过引入非均匀网格进一步提高精度，同时保持稳定性；(5)我们的方法依赖于成熟的多重网格方法，允许在不同的长度尺度上加速收敛到适当的解；(6)代码将在开放源码GPL许可下开发，并作为现有代码(如AMBER)的“附加”包向公众提供；(Vii)代码将是可扩展和可移植的，可在大规模并行的超级计算机和工作站上运行。他们将使用现代基于Web的技术来提供访问模拟和结果的途径。新的能力将使我们能够解决关键挑战和聚合生物分子问题，如酶反应、凝血蛋白和其他问题，作为我们ITR计划的一部分，并通过整个科学界的努力。最终，我们将通过GPL许可证将我们的代码免费分发给生物模拟社区，以实现成果的广泛传播和最大的科学影响。除了研究目标外，该项目还有相当大的教育目标，旨在开发一套跨学科的现代课程，以激发学生对计算和模拟科学与技术的兴趣和兴奋。为此，我们将为NCSU目前正在形成的高性能超级计算中心开发一个课程，建立一套教育工具，将在学生和博士后暑期研讨会期间介绍和传播。%