Development of a Next-Generation Nucleic Acid Force Field

项目摘要/摘要 生物分子模拟是分析生物聚合物结构和动力学的重要工具， 研究分子间相互作用，设计新的配体和药物。模拟，在 转向，完全依赖于底层结构的准确和高效的模型 化学和能量学中的经验能量函数(“力场”)。力场 技术目前正处于从传统的以原子为基础的观点的代际过渡中 使用更好的静电模型，电荷朝向更复杂和准确的电势。这 建议继续发展阿米巴(原子多极优化能量学) 生物分子应用)用于核酸(Nas)的力场，并扩大了 对天然和人工修饰的NA组分进行建模。加上我们2013年的阿米巴 蛋白质参数，新的NA力场将为最重要的 生物分子系统。目前的NA力场远远落后于它们的蛋白质对应场 能够在生理条件下对最典型的结构进行精确建模。这个 下一代阿米巴NA力场有望显著提高保真度和射程 核酸模型的研究。 核酸是携带生命信息的主要分子。在这项研究项目下， 我们将研究核酸的几个关键方面，并完善阿米巴力场。这个 NAS的结构和功能高度依赖于盐环境。相互影响 在RNA局部结构动力学和全局/三级折叠之间是一个有趣的问题 通过实验解决。模拟结合能量学和设计小分子的能力 药物和合成修饰的寡核苷酸将是未来的重要增长领域 医学上的进步。这些研究将与实验部门密切合作进行 同事们。开发精确的、可转移的下一代力场将开启 为理解和预测天然和设计的核的行为开辟了新的途径 酸性分子。 最后，在更长的时间尺度上对大型结构进行足够的抽样对未来至关重要。 分子模拟。建议开发高性能、开源、并行的 计算机软件将使阿米巴力场在原子核上得到广泛应用 酸和相关的生物分子系统。

PROJECT SUMMARY/ABSTRACT Biomolecular simulation is a critical tool for analysis of biopolymer structure and dynamics, investigation of intermolecular interactions, and design of new ligands and drugs. Simulation, in turn, is absolutely dependent on accurate and efficient models of the underlying structural chemistry and energetics in terms of empirical energy functions (“force fields”). Force field technology is currently in the midst of a generational transition from traditional atom-based point charges towards more intricate and accurate potentials using better electrostatic models. This proposal will continue development of the AMOEBA (Atomic Multipole Optimized Energetics for Biomolecular Applications) force field for nucleic acids (NAs), and extend the coverage of the model to naturally and synthetically modified NA components. Coupled with our 2013 AMOEBA protein parameters, the new NA force field will provide a unified model for the most important biomolecular systems. Current NA force fields lag well behind their protein counterparts in their ability to accurately model even the most typical structures under physiological conditions. The next-generation AMOEBA NA force field promises to significantly improve the fidelity and range of nucleic acids modeling. Nucleic acids are the major information carrying molecules of life. Under this research project, we will investigate several key aspects of nucleic acids, and refine the AMOEBA force field. The structures and functions of NAs are highly dependent upon the salt environment. The interplay between RNA local structural dynamics and global/tertiary folding is an intriguing question being addressed experimentally. The ability to model binding energetics, and design small molecule drugs and synthetically modified oligonucleotides will be an important growth area for future medical advances. These studies will be carried out in close collaborations with experimental colleagues. Development of an accurate and transferable next-generation force field will open up new paths toward understand and prediction of the behavior of natural and designed nucleic acid molecules. Finally, adequate sampling of large structures over longer time scales is crucial for future molecular simulations. The proposed development of high-performance, open source, parallel computer software will enable widespread application of the AMOEBA force field to nucleic acids and related biomolecular systems.