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）倡议的提案的结果。 该赠款由材料研究，化学，生物基础设施以及分子和细胞生物科学部门共同资助。 大规模的电子结构和原子模拟已经被证明是必不可少的，在推进我们的理解的复杂的物理和化学的生物分子在执行其细胞功能的转换。 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生物分子过程提供了前所未有的机会，即，通过对基本自然规律和过程的计算机表示进行精确建模。 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，将实用性、灵活性、准确性和科学影响力提高到一个新的质量水平。 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近的算法进步来实现。 真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模拟。 虽然理想情况下，人们希望以从头算的准确性来描述生物分子及其所有转换，但考虑到此类模拟的计算需求，这显然是一个不合理的目标。 然而，什么是触手可及的是一个综合的多尺度方法，根据其重要性，以不同的精度水平处理生物分子系统的不同部分。 例如，为了理解酶促反应，需要尽可能准确地理解由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将大型系统分解为一组重叠的嵌套区域（量子，经典，或连续），并开发接口，提供了一个物理上一致的描述，并保持基本的物理定律完好无损。为了实现这些目标，我们的目标是开发一套模块化的生物分子模拟工具，在量子，经典的原子或连续水平，如大分子复合物的有效研究所需。 在量子水平上，我们将处理系统的量子蒙特卡罗（QMC），量子化学后Hartree-Fock和密度泛函方法（DFT）的组合。 在中间水平，将使用经验力场的经典分子动力学，而连续介质方法可以用来描述溶剂环境的大长度尺度特性。 为了构建这样的工具，需要在物理表示的每个“层次”上开发对当前方法的实质性算法改进，同时沿着系统的不同描述之间的适当接口。 我们的方法的最重要的创新特征将是：（i）前所未有的使用高精度QMC方法及其生物模拟的新发展;（ii）在密度泛函水平上，算法的改进将使得能够对数千个原子进行常规计算，包括量子分子动力学，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）静电相互作用将在经典力学区域中以高度精确的方式处理，并实施点多极展开，极化率和低阶连续波函数，这将提供量子和经典区域之间的鲁棒界面;（iv）代码将基于实空间网格，因为这些网格能够在并行机器上实现真正的O（N）缩放，在边界条件方面更加灵活，并允许额外的增益精度，同时保持稳定性，通过引入非均匀网格;（v）我们的方法依赖于成熟的多重网格方法，允许加速收敛到适当的解决方案在不同的长度尺度;（vi）这些代码将在开放源码GPL许可下开发，并作为现有代码（如AMBER）的“附加”软件包向公众提供;（vii）这些编码将可按比例缩放和便携，可在大规模并行超级计算机和工作站上运行。 他们将利用现代网络技术提供模拟及其结果的访问。新的能力将使我们能够解决关键挑战和典型的生物分子问题，如酶反应，凝血蛋白等，这既是我们ITR计划的一部分，也是整个科学界的努力。 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，以实现结果的广泛传播和最大的科学影响。 除了研究目标外，该计划还具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，我们将为目前在NCSU成立的高性能超级计算中心开发课程，建立一套教育工具，这些工具将在学生和博士后的夏季研讨会上介绍和传播。