PRAC - Ensembles of molecular dynamics engines for assessing force fields, conformational change, and free energies of proteins and nucleic acids

该项目使用Amber程序套件中的计算机模拟方法来模拟蛋白质和核酸在其自然环境中的原子运动，以更好地了解各种生物分子的结构、动力学和相互作用。通过对结果数据的分析，模拟提供了对生物分子功能以及如何调节功能的洞察。成功的关键是对生物分子的复杂构象分布进行足够的采样，并使用潜在原子相互作用或“力场”的准确表示。为了便于采样，该项目将在CPU和GPU资源上并行优化的独立模拟集合耦合在一起，交换信息以提高采样效率。Blue Waters超级计算机的初步工作已经证明，对RNA四核苷酸、四环RNA结构以及B-DNA螺旋的内部部分的构象分布进行了可重复和完整的采样。有了完整的采样，现在就可以可靠地评估、验证和改进所施加的力场。更广泛的影响集中在模拟方法和力场的改进上，被广泛的研究人员应用于从药物设计到破译结构-功能关系的应用。通过开发、优化和应用温度和哈密顿空间中的多维副本交换方法来提高构象采样的效率。琥珀分子动力学模拟代码经过了极好的优化，适用于Blue Waters上的GPU资源。对Blue Waters的初步模拟表明，尽管有可能收敛RNA四核苷酸和四环核苷酸等核酸的构象分布，但人们没有发现与实验完全一致的构象分布。换句话说，核酸的力场仍然存在严重的缺陷，正在发现并克服这些缺陷，以改进模型。为了进一步探索溶液条件下的核酸和蛋白质结构，还对室温晶体进行了模拟，这为评估和验证模拟方法提供了另一种手段。更大、更具代表性的蛋白质和核酸结构也在研究中。

This project uses computer simulation methods within the AMBER suite of programs to simulate the atomic motions of proteins and nucleic acids in their native environment to better understand the structure, dynamics and interactions among various bio-molecules. Through analysis of the resulting data, the simulations provide insight into biomolecular function and how to modulate function. Critical to success is adequate sampling of the complex conformational distributions of the biomolecules and also use of an accurate representation of the underlying atomic interactions or "force field". To facilitate sampling, the project couples together ensembles of independent simulations, optimized in parallel on CPU and GPU resources, that exchange information to increase sampling efficiency. Preliminary work on the Blue Waters Supercomputer has demonstrated reproducible and complete sampling of the conformational distributions of RNA tetranucleotides, tetraloop RNA structures, and also the internal portion of a B-DNA helix. With complete sampling, it is now possible to reliably assess, validate, and improve the applied force fields. Broader impacts center on the improvements in both the simulation methods and force fields, in wide use by a broad community of researchers in applications ranging from drug design to deciphering structure-function relationships.Increases in the efficiency of conformational sampling are realized by developing, optimizing and applying multi-dimensional replica exchange methods in temperature and Hamiltonian space. The AMBER molecular dynamics simulation codes are extremely well optimized and suited to the GPU resources on Blue Waters. Preliminary simulations on Blue Waters, reducing times to solution from months-years to days-weeks, show that although it is possible to converge the conformational distributions of nucleic acids like RNA tetranucleotides and tetraloops, one does not find conformational distributions that completely agree with experiments. In other words, there are still serious deficiencies in the force fields for nucleic acids that are being uncovered and overcome to improve the models. To further the exploration of nucleic acid and protein structures beyond solution conditions, simulations are additionally being performed on room temperature crystals which provide an additional means to assess and validate the simulation approaches. Larger and more representative protein and nucleic acid structures are also being investigated.