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

描述(申请人提供)：对核酸结构进行末期精炼的生物分子模拟：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学模拟方法对核酸结构进行“末期”细化，特别关注RNA的结构、功能和药物靶向。为此，我们将提炼表示核酸结构的经验力场，探索动力学(包括水、盐、蛋白质和其他相互作用的配体环境对性质的可弯曲性、可扭性和改变)，并评估典型模型结构的性能。我们的一套完整的假设是：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“末期”改进和排序，以及(2)更好地理解假定的药物与核酸的相互作用。此外，(3)通过提供各种不同核酸的大集合MD轨迹的数据集和分析，社区将更快地了解MD数据在多个尺度上表示核酸结构、动力学和相互作用的强度、局限性和用途。我们的目标是对假定的RNA模型的相对重要性进行提炼和排名。换句话说，给定假定的满足二级结构约束的三维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名。除了一大套常见和具有代表性的DNA和RNA结构基序外，其应用还包括研究高度修饰的tRNAlys与HIV1-A环相互作用的模型系统中的密码子-反密码子相互作用，优化RNA膨胀的靶向药物，以及详细描述DNA微环和核小体定位序列中的序列特异性结构和动力学。这些研究不仅提供了对核酸结构和动力学的基本见解，还为开发针对核酸结构的计算机辅助药物设计策略提供了基础(在从癌症到抗生素的各种应用中)，并将展示生物分子模拟在破译核酸结构/功能关系方面可以发挥的重要作用。使用先进的原子模拟方法，我们将对核酸结构进行“末期”改进，重点放在RNA结构、功能和药物靶向上，并探索一种新的数据传播模式，在这种模式下，我们的原始模拟结果可以向更大的社区提供。这些研究不仅提供了对核酸结构和动力学的基本见解，还为开发针对核酸结构的计算机辅助药物设计策略提供了基础(在从癌症到抗生素的各种应用中)，并将展示生物分子模拟在破译核酸结构/功能关系方面可以发挥的重要作用。

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.