Biomolecular simulation for the end-stage refinement of nucleic acid structure

项目总结/摘要 尽管生物分子模拟方法在性能和可靠性方面取得了重大进展，但非生物分子模拟方法仍然是一种非常有效的方法。 螺旋核酸结构被证明难以用目前可用的方法完全和准确地建模 生物分子力场这项研究旨在评估，验证和改善核酸的力场， 也为了更好地理解模型DNA和RNA系统的真实构象系综， 使用最大熵方法进行实验。这不仅包括对主导的 构象，但也激发态或低人口状态。模型系统包括RNA二核苷酸，RNA 四核苷酸、RNA四环、DNA迷你哑铃和NMR衍生的NMR结构，已知它们 填充多个结构或激发态。采用的方法包括最先进的多维 复制交换分子动力学（M-REMD）模拟和各种NMR方法提供更多 深入了解新的四核苷酸结构（NOE，J-偶联等）对于激发态，通过NMR 弛豫和NMR弛豫分散实验。M-REMD代码将被扩展， 异步集成实例（用于提高效率和队列回填）和自适应性， 动态分析以评估收敛性，以及需要更多/更少集合实例的情况。各种 改进力场的方法包括对收敛的MD弹道重新加权的替代方法 集合和项目自由能表面与多态班尼特验收比方法作为一个功能 在可能的情况下，通过参数扫描，通过拟合高水平基底-基底相互作用，改变力场参数 高量子力学的能量，小模型化合物适合液体密度和其他方法。此外，本发明还提供了一种方法， 该小组将与“开放力场计划”合作，调整、评估和验证他们的小分子部队 到核酸。使用M-REMD方法，该团队已经证明了对构象进行完全采样的能力。 在GPU上进行大规模计算的所提出的模型系统的集成，具有多种不同的力 领域的该小组在DNA和RNA的大规模模拟方面拥有相当丰富的经验， 合作记录以及研究结果和成果的传播。制定更好的方法， 核酸的结构、动力学和相互作用的模拟提供了接近药物的手段， 能力和设计新的治疗方法，并提供更深入的了解结构，动力学的作用， 以及功能上的构象变化，这在基础科学水平上提供了独特的能力， 如果使这些方法正确和准确地发挥作用，就有相当大的健康相关性。

Project Summary / Abstract Despite significant advances in the performance and reliability of biomolecular simulation approaches, non- helical nucleic acid structures are proving difficult to fully and accurately model with currently available biomolecular force fields. This research aims to assess, validate, and improve force fields for nucleic acids, and also to better understand the true conformational ensemble of model DNA and RNA systems by best fits to NMR experiment using Maximum Entropy methods. This includes characterization of not only the dominant conformations, but also excited states or low population states. Model systems include RNA dinucleotides, RNA tetranucleotides, RNA tetraloops, DNA mini-dumbbells, and NMR-derived NMR structures that are known to populate multiple structures or excited states. Methods employed include state-of-the-art multi-dimensional replica-exchange molecular dynamics (M-REMD) simulations and various NMR approaches to provide more insight into new tetranucleotides both in structure (NOE, J-coupling, etc.) and for excited states via NMR relaxation and NMR relaxation dispersion experiments. The M-REMD code will be extended to allow asynchronous ensemble instances (for greater efficiency and queue backfill) and adaptivity and steering with on-the-fly analyses to assess convergence and where more/fewer ensemble instances are needed. Various approaches to force field improvement include surrogate methods for re-weighting converged MD trajectory ensembles and project free energy surfaces with Multistate Bennett Acceptance Ratio methods as a function of force field parameter change, where possible, via parameter scanning, via fits to high level base-base interaction energies from high level QM, and small model compound fits to liquid densities and other methods. In addition, the group will work with the Open Force Field Initiative to adapt, assess, and validate their small molecule force fields to nucleic acids. Using M-REMD methods the team has proven the ability to fully sample the conformational ensemble of the proposed model systems with large-scale computation on GPUs with multiple different force fields. The group has considerable experience in large-scale simulation of DNA and RNA and a proven track record of collaboration and dissemination of research findings and results. Development of better methods for simulation of the structure, dynamics and interactions of nucleic acids provides the means to approach drug- ability and the design of novel therapeutics, and also to provide greater insight into the role of structure, dynamics and conformational change in function which at a basic science level provides unique capabilities that could have considerable health relevance if the methods are made to function correctly and accurately.