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

描述（由申请人提供）：用于核酸结构末端细化的生物分子模拟：核酸的结构、动力学和相互作用是其功能的基础。我们的目标是利用先进的原子模拟方法来执行核酸结构的“最终阶段”细化，特别关注RNA结构，功能和药物靶向。为此，我们将完善代表核酸结构的经验力场，探索动力学（包括可弯曲性、可扭转性以及水、盐、蛋白质和其他相互作用配体环境对性质的改变），并评估代表性模型结构的性能。我们的综合假设是：使用改进的经验力场和改进的分子动力学和自由能模拟协议（包括增强的采样方法），我们可以(1)对假定的RNA模型结构进行“最终阶段”的细化和排序，(2)更好地理解假定的药物与核酸的相互作用。此外，(3)通过提供各种核酸的大量MD轨迹的数据集和分析，社区将更快地了解MD数据在多尺度上表示核酸结构、动力学和相互作用的优势、局限性和用途。我们的目标是完善和排序假定的RNA模型的相对重要性。换句话说，给定满足二级结构限制的假定三维RNA模型，我们相信我们可以使用模拟来更接近正确的原子结构，并且我们可以对给定模型的相对重要性或可靠性进行排序。除了大量常见和具有代表性的DNA和RNA结构基序外，应用还包括研究与HIV1-A环相互作用的超修饰tRNAlys模型系统中的密码子-反密码子相互作用（对病毒的起始很重要），优化RNA膨化靶向药物，以及DNA微环和核小体定位序列中序列特异性结构和动力学的详细表征。这些研究，除了提供对核酸结构和动力学的基本见解之外，还为针对核酸结构的计算机辅助药物设计策略的发展提供了基础（应用范围从癌症到抗生素），并将证明生物分子模拟在破译核酸结构/功能关系方面可以发挥重要作用。使用先进的原子模拟方法，我们将执行核酸结构的“最终阶段”细化，特别关注RNA结构，功能和药物靶向，并探索一种新的数据传播模型，其中我们的原始模拟结果可用于更大的社区。这些研究，除了提供对核酸结构和动力学的基本见解之外，还为针对核酸结构的计算机辅助药物设计策略的发展提供了基础（应用范围从癌症到抗生素），并将证明生物分子模拟在破译核酸结构/功能关系方面可以发挥重要作用。

DESCRIPTION (provided by applicant): Biomolecular simulation for the end-stage refinement of nucleic acid structure: The structure, dynamics, and interactions of nucleic acids are fundamental to their function. Our aim is to utilized advanced atomistic simulation methods to perform the "end-stage" refinement of nucleic acid structure with a specific focus on RNA structure, function and drug targeting. To do this, we will refine empirical force fields for representing nucleic acid structure, explore the dynamics (including bendability, twistability and alteration of the properties by the environment of water, salt, proteins and other interacting ligands), and assess the performance on representative model structure. Our integrated set of hypothesis are that: Using improved empirical force fields and improved molecular dynamics and free energy simulation protocols (including enhanced sampling methods), we can (1) perform the "end-stage" refinement and ranking of putative RNA model structures and (2) better understand the interaction of putative drugs with nucleic acids. Moreover, (3) by making datasets and analyses of large sets of MD trajectories of varied nucleic acids generally available, the community will move forward faster in understanding the strengths, limitations, and uses of MD data for representing nucleic acid structure, dynamics, and interaction at multiple scales. It is our aim to refine and rank the relative importance of putative RNA models. In other words, given putative three-dimensional RNA models that satisfy secondary structure restraints, we believe that we can use simulation to move closer to the correct atomic structure and that we can rank the relative importance or reliability of a given model. Applications, beyond a large set of common and representative DNA and RNA structure motifs, include a study of codon-anticodon interactions in the model system of hypermodified tRNAlys interacting with the HIV1-A loop (important for initiation of the virus), optimizing RNA bulged targeting drugs, and detailed characterization of sequence specific structure and dynamics in DNA minicircles and nucleosome positioning sequences. Such studies, beyond providing fundamental insight into nucleic acid structure and dynamics, provide a basis for the development of computer-aided- drug-design strategies for targeting nucleic acid structure (in applications ranging from cancer to antibiotics) and will demonstrate the important role biomolecular simulations can play in deciphering nucleic acid structure / function relationships. Using advanced atomistic simulation methods we will perform the "end-stage" refinement of nucleic acid structure with a specific focus on RNA structure, function and drug targeting and explore a novel data dissemination model where our raw simulation results are made available to the larger community. Such studies, beyond providing fundamental insight into nucleic acid structure and dynamics, provide a basis for the development of computer-aided-drug-design strategies for targeting nucleic acid structure (in applications ranging from cancer to antibiotics) and will demonstrate the important role biomolecular simulations can play in deciphering nucleic acid structure / function relationships.