Development of a Next-Generation Nucleic Acid Force Field

项目总结/摘要 核酸（Nucleic Acids，NAs）是生命的主要信息载体。能够使用 对DNA和RNA的结构、动力学和相互作用进行建模的计算是一个关键的辅助手段 这些生物分子的实验研究。例如，含有假尿苷的mRNA 新型冠状病毒疫苗是抗击疫情的重要工具。DNA、mRNA和 miRNA是许多抗菌和抗病毒药物的靶点。小分子设计 在癌症和神经变性疾病的治疗中与核酸结合的药物 这是当前制药研究的最热门话题之一。在这个项目中，我们将 研究核酸的几个关键方面，并开发可极化多极 AMOEBA+模型用于模拟NAs及其相互作用。这种新的力场将进一步 通过将局部价特征的基于机器学习的势与 经典的长程非键相互作用。由此产生的AMOEBA+NN力场承诺 NA系统结合计算的化学准确性。AMOEBA+的参数 和AMOEBA+NN电位将使用新的自动Poltype 2包生成。 将力场应用到现有的支持GPU的Tinker 9分子动力学中 软件将能够进行最先进的模拟和结合自由能估算。 分子模拟对治疗设计的适用性受到效率和 计算的准确性。该提案的目的是使常规、准确 计算小分子配体与NAs结合的热力学。朝向 最后，将研究几种当前的生物相关系统，包括 G-四链体结构的金属离子，与RNA适体的荧光配体，新型抗生素 药物与FMN核糖开关，和构象动力学的P5 abc结构域的 四膜虫I组核酶。NA的结构和功能高度依赖于 离子环境。RNA局部结构动力学与全局/三级结构动力学之间的相互作用 折叠是一个有趣的问题，正在通过实验来解决。模拟这些的能力 复杂的能量效应在设计新型小分子药物和合成修饰 寡核苷酸将是未来医学发展的重要增长领域。发展 精确和可转移的下一代AMOEBA+和AMOEBA+NN力场将 为理解和预测自然和设计的行为开辟了新的途径 核酸分子。

PROJECT SUMMARY/ABSTRACT Nucleic acids (NAs) are the major information carrying molecules of life. The ability to use computation to model the structure, dynamic and interactions of DNA and RNA is a key adjunct to experimental study of these biomolecules. For example, pseudouridine-containing mRNA vaccines against Covid-19 are a critical tool in battling the pandemic. DNAs, mRNAs, and miRNAs are targets for a number of antibacterial and antiviral drugs. Design of small molecule drugs binding to nucleic acids in the treatment of cancers and neurodegenerative diseases is one of the hottest topics of current pharmaceutical research. Under this project, we will investigate several key aspects of nucleic acids, and develop the polarizable multipole AMOEBA+ model for simulation of NAs and their interactions. This new force field will be further enhanced via coupling of a machine learning-based potential for local valence features with classical long-range nonbonded interactions. The resulting AMOEBA+NN force field promises chemical accuracy in the calculation of binding for NA systems. Parameters for the AMOEBA+ and AMOEBA+NN potentials will be generated using the new, automated Poltype2 package. Implementation of the force fields into the existing GPU-capable Tinker9 molecular dynamics software will enable state-of-the-art simulation and binding free energy estimation. The applicability of molecular simulation to design of therapeutics is limited by efficiency and accuracy of the calculations. The objective of this proposal is to enable routine, accurate computation of the thermodynamics of binding of small-molecule ligands to NAs. Toward that end, several current systems of biological relevance will be investigated, including binding of metal ions to G-quadruplex structures, fluorogenic ligands with RNA aptamers, novel antibiotic drugs with the FMN riboswitch, and conformational dynamics of the P5abc domain of the Tetrahymena group I ribozyme. The structures and functions of NAs are highly dependent upon their ionic environment. The interplay between RNA local structural dynamics and global/tertiary folding is an intriguing question being addressed experimentally. The ability to simulate these complex energetic effects in the design of novel small molecule drugs and synthetically modified oligonucleotides will be an important growth area for future medical advances. Development of the accurate and transferable next-generation AMOEBA+ and AMOEBA+NN force fields will open new paths toward understand and prediction of the behavior of natural and designed nucleic acid molecules.