Software for the accurate de novo 3D structure prediction of RNA

描述(由申请人提供)：从基因组测序项目中发现新的和有趣的RNA序列，以及解开其功能的紧迫性，导致了对新的结构确定技术的戏剧性推动。目前用于确定核酸三维结构的实验方法，如X射线结晶学和核磁共振，不能跟上日常发现的需要解决或模拟典型结构的序列的步伐。因此，显然需要开发用于仅给出主序列和当可用时实验约束信息的3D结构预测的工具。与蛋白质相比，RNA结构预测得到的资源有限，直到最近才受到科学界的关注。因此，尽管蛋白质和核酸之间存在巨大的内在差异，但RNA预测在很大程度上依赖于蛋白质预测方法。虽然许多这些工具在预测质量方面取得了重大进展，但它们也显示出可靠性较低，而且往往仅限于对非常小的RNA的预测。此外，大多数是手动或半自动的，这需要有经验的用户和各种中间软件包。为了解决这些问题，DNA Software，Inc.(DNAs)开发了一款RNA同源建模软件NA-CAD(核酸计算机辅助设计)，该软件具有专门为RNA优化的独特力场。该工具已经成功地对大型RNA-蛋白质复合体进行了同源建模，例如铜绿假单胞菌的小核糖体亚单位。我们现在想要扩展NA-CAD以包括用于从头结构预测的组件。NA-CAD中的力场和我们的旗舰软件产品VisualOMP中基于自由能的二级结构预测算法为开发能够准确地从头开始预测中大型RNA靶的三级结构的统一工具提供了有利的起点。这项建议致力于设计新的算法来处理复杂的结构主题，如多环、伪结点和多个结构域，并结合实验约束来提高预测质量。此外，将实施表示RNA残基的粗粒度模型和加速的经典分子动力学模拟，以在易于处理的计算时间框架内增加构象采样。 公共卫生相关性：我们建议开发一种准确、快速和统一的从头结构预测工具，针对中到大型RNA进行优化。这一工具将产生有价值的结构模型，有助于阐明没有已解决的晶体或核磁共振结构的RNA的功能。建议的从头开始工具将被整合到我们的同源建模软件NA-CAD中，这样它将能够生成与药物相关的RNA靶标的三维同源模型，并对潜在的耐药突变进行建模，这将有利于参与基于结构的药物发现的研究人员。

DESCRIPTION (provided by applicant): The discovery of new and interesting RNA sequences from genome sequencing projects, and the urgency to unravel their functions, has led to a dramatic push for novel structural determination techniques. Current experimental methods for three dimensional structure determination of nucleic acids such as x-ray crystallography and NMR cannot keep pace with the day to day discovery of sequences that need representative structures to be solved or modeled. Thus, there is a clear need to develop tools for 3D structure prediction given only the primary sequence and when available, experimental constraint information. Compared to proteins, RNA structure prediction has received limited resources, and only recently has the field gained attention by the scientific community. As such, RNA prediction has largely relied on protein prediction methodologies despite the vast intrinsic differences between proteins and nucleic acids. Although many of these tools have shown significant advances in the prediction quality, they have also demonstrated low reliability and are often limited to prediction of very small RNAs. In addition, the majority are either manual or semi-automated, which requires an experienced user and a variety of intermediate software packages. To address such concerns, DNA Software, Inc. (DNAS) has developed an RNA homology modeling software, NA-CAD (Nucleic Acid Computer Aided Design) that has a unique force field specifically optimized for RNA. This tool has demonstrated success in homology modeling of large RNA-protein complexes such as the small ribosomal subunit of Pseudomonas aeruginosa. We would now like to extend NA-CAD to include a component for de novo structure prediction. The force field in NA-CAD and the free energy based secondary structure prediction algorithm in our flagship software product Visual OMP provide an advantageous starting point for developing a unified tool that can accurately predict de novo the tertiary structure of medium to large RNA targets. This proposal addresses the engineering of novel algorithms for handling difficult structural motifs such as multiloops, pseudoknots, and multiple domains and incorporating experimental constraints to improve prediction quality. Additionally, coarse-grained models for representing RNA residues and accelerated classical molecular dynamics simulations will be implemented to increase conformational sampling in a tractable computational time frame. PUBLIC HEALTH RELEVANCE: We propose to develop an accurate, fast, and unified de novo structure prediction tool optimized for medium to large sized RNAs. This tool will generate valuable structural models that will help elucidate the functions of RNAs that do not have solved crystal or NMR structures. The proposed de novo tool will be incorporated into our homology modeling software, NA-CAD, so that it will be able to generate three-dimensional homology models of pharmaceutically relevant RNA targets and to model potential drug-resistant mutants, which will be beneficial to researchers involved in structure-based drug discovery.