PRAC - Ensembles of Molecular Dynamics Engines for Assessing Force Fields, Conformational Change, and Free Energies of Proteins and Nucleic Acids

PRAC - 用于评估力场、构象变化以及蛋白质和核酸自由能的分子动力学引擎集合

• 批准号: 1515572
• 负责人: Thomas Cheatham
• 金额: $ 4万
• 依托单位: University of Utah
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2019-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1515572&HistoricalAwards=false
• 关键词: PRAC; Ensembles; Molecular; Dynamics; Engines

Using the Blue Waters petascale resource, our research centers on developing and applying accurate methods for the simulation of biomolecules using the AMBER software. Using ensembles of these simulations, we can efficiently model the conformational distributions of biomolecules to better understand their structure, dynamics and interactions, and ultimately this provides detailed information about their function. This information can be used to design drugs to modulate function and to help determine how to alter the biomolecular structure and dynamics to influence function. Over the past few years, using these technologies we have shown the ability to reproducibly converge the conformational distributions (i.e. the set of conformations sampled under a particular set of conditions, such as at a particular temperature, pH, or specific environment) of various RNA molecules. We have also improved the molecular "force fields" that allow proper modeling of the structure and dynamics. This generally allows us to better understand how biomolecular machines, including various protein and RNA molecules, function. For example, one of our goals is to understand how riboswitches recognize specific metabolites which in turn leads to conformational changes that alters regulation of those metabolites. Another goal is to better understand the structure and dynamics of biomolecules in the crystal and this will lead to a better understanding of the role of structure and disorder in protein function. The methods and "force fields" developed are in wide use by a larger community that is aiming to provide realistic insight into biomolecular structure, dynamics, and function. Although not all research groups have access to the Blue Waters petascale resource at this time, the technology we are developing and applying now will become routinely accessible to the larger community who can then easily apply these methods on future resources. Since computer power and accessibility continues to grow at a rapid pace, the broader community will see the impact of these technologies within a few years.Advances in simulation methods and increases in computational power have coupled together over the past few decades to transform our understanding of biological macromolecules; we can watch small proteins fold to their correct structure, we can help design new therapeutics, and improved simulation methods can help refine low resolution or ambiguous experimental data. The biomolecular simulation methods we apply add to experimental data by exposing information not readily measured about the motions of biomolecules across many size and time scales, ranging from the fastest bond vibrations to slower collective motions. This allows elucidation of the dynamic landscape of proteins and nucleic acids as a function of time, especially at smaller scales. Access to petascale computational resources allows us for the first time to fully explore the structural, dynamic and energetic landscape of complex biomolecules. In our current PRAC, we have been able to fully converge the conformational ensemble of DNA helices, RNA tetranucleotides and tetraloops, we assessed and improved the force fields, and we also developed novel multi-dimensional replica-exchange methods and analysis tools. With further collaboration of an experienced team of AMBER developer?s, we aim to decipher the full landscape of protein and nucleic acid structure and function, with a heavy focus on RNA, DNA and proteins and their complexes. On Blue Waters we will continue to hierarchically and tightly couple ensembles of highly GPU optimized molecular dynamics engines to fully map out the conformational, energetic and chemical landscape of biomolecules. This will be done not only to assess, validate and improve currently available biomolecular force fields, but also to provide novel insight into DNA structure in the crystal and in solution, RNA riboswitch dynamics and function, and also protein-nucleic acid interactions. Additional aims focus on the development of new analysis methods and dissemination of the simulation data to the larger community for deeper and broader inspection.

利用Blue沃茨千万亿次资源，我们的研究中心致力于开发和应用使用AMBER软件模拟生物分子的精确方法。使用这些模拟的集合，我们可以有效地模拟生物分子的构象分布，以更好地了解它们的结构，动力学和相互作用，并最终提供有关其功能的详细信息。这些信息可用于设计药物以调节功能，并帮助确定如何改变生物分子结构和动力学以影响功能。在过去的几年里，使用这些技术，我们已经证明了可重复地收敛各种RNA分子的构象分布（即在特定条件下采样的构象集，例如在特定温度，pH值或特定环境下）的能力。我们还改进了分子“力场”，使结构和动力学的适当建模。这通常使我们能够更好地了解生物分子机器，包括各种蛋白质和RNA分子的功能。例如，我们的目标之一是了解核糖开关如何识别特定的代谢物，从而导致构象变化，改变这些代谢物的调节。另一个目标是更好地理解晶体中生物分子的结构和动力学，这将导致更好地理解结构和无序在蛋白质功能中的作用。开发的方法和“力场”被更大的社区广泛使用，旨在提供对生物分子结构，动力学和功能的现实洞察。尽管目前并非所有研究小组都可以使用蓝沃茨千万亿次资源，但我们现在正在开发和应用的技术将成为更大社区的常规技术，然后他们可以轻松地将这些方法应用于未来的资源。 由于计算机能力和可访问性继续快速增长，更广泛的社区将在几年内看到这些技术的影响。在过去的几十年里，模拟方法的进步和计算能力的增加结合在一起，改变了我们对生物大分子的理解;我们可以观察小的蛋白质折叠成正确的结构，我们可以帮助设计新的治疗方法，改进的模拟方法可以帮助改进低分辨率或模糊的实验数据。 我们应用的生物分子模拟方法通过暴露关于生物分子在许多尺寸和时间尺度上的运动不容易测量的信息来添加实验数据，范围从最快的键振动到较慢的集体运动。这允许阐明蛋白质和核酸作为时间的函数的动态景观，特别是在较小的尺度上。 获得千万亿次计算资源使我们能够第一次充分探索复杂生物分子的结构，动态和充满活力的景观。 在我们目前的PRAC中，我们已经能够完全收敛DNA螺旋，RNA四核苷酸和四环的构象系综，我们评估和改进的力场，我们还开发了新的多维复制交换方法和分析工具。 与经验丰富的AMBER开发团队进一步合作？我们的目标是破译蛋白质和核酸结构和功能的全部景观，重点关注RNA，DNA和蛋白质及其复合物。在Blue沃茨上，我们将继续分层并紧密耦合高度GPU优化的分子动力学引擎，以全面绘制生物分子的构象，能量和化学景观。 这将不仅是为了评估，验证和改善目前可用的生物分子力场，而且还提供了新的见解，在晶体和溶液中的DNA结构，RNA核糖开关动力学和功能，以及蛋白质-核酸相互作用。 其他目标侧重于开发新的分析方法和向更大的社区传播模拟数据，以进行更深入和更广泛的检查。