An all-in-one web server for RNA structure prediction using evolutionary information

工程摘要 RNA的结构和功能密切相关。为了弄清楚转录组中无数的RNA是什么 我们需要严格的方法来推断结构。许多预测算法已经存在，但它们 输出模型的任何和每一个序列，不同的方法往往输出不同的模型， 相同的序列。这导致了次优模型渗透到该领域，并将结构归因于RNA 它们实际上没有任何保守的结构。RNA研究领域现在需要的是一个 计算工具，其将评估特定RNA序列具有生物结构的可能性，以及 以最高的准确度提出该结构。长期以来，解决这个问题的最佳方法是 不同生物体同源序列的比较。同样的方法实际上是基于 最成功的蛋白质结构预测工具。但是，这种方法广泛采用的一个障碍是， 预测RNA结构的关键是序列比较需要计算方面的知识和专业知识， 和结构生物学，以及使用非主流工具。这份提案是关于 开发一个免费的网络服务器，用于可靠地预测RNA二级和最终三级 使用进化信息的结构。这个web服务器将作为一套工具（ 其输出将提供给感兴趣的用户），从同源序列检索到 产生的模型。首先，该工具将自动检索和比对同源序列， 现有的和新的算法。该目的将搜索与任何单个序列相关的同源物， 输入，这是目前大多数方案尚未满足的挑战。第二，应用程序使用 共变异分析将解决输入RNA序列具有保守结构的可能性， 因此，并非用作输入的每个序列都必须输出结构模型。后续模块 在线工具将评估校准的质量，并可能改进此校准， 具有置信度分数的情况。不管结果如何，用户都会得到一个结果， 考虑到进化以及最新的RNA结构信息，因此它不会因使用 单个参数集，如现有预测方法通常的情况。一个更全面的， 利用进化信息的简单计算工具将有助于传播这些信息的使用。 方法，以更大的RNA生物学社区，最大限度地影响RNA研究的实验设计。

Project Abstract RNA structure and function are intimately linked. To sort out what the myriad RNAs in transcriptomes are doing, we need rigorous approaches that also infer structure. Many predictive algorithms already exist, but they output models for any and every sequence, and different approaches often output different models for the same sequence. This results in suboptimal models that permeate the field, and in ascribing structure to RNAs that don't in fact have any conserved structure. What the field of RNA research needs now to go forward is a computational tool that will evaluate the likelihood that a certain RNA sequence has a biological structure, and propose that structure with the highest accuracy. The best approach to this issue has been for a long time the comparison of homologous sequences from diverse organisms. This same approach is actually at the basis of the most successful protein structure prediction tools. But a hindrance in the wide adoption of such approaches for predicting RNA structure is that sequence comparison requires knowledge and expertise in computational and structural biology as well as access to tools that are not mainstream. This proposal is about the development of a freely available webserver for reliably predicting RNA secondary and eventually tertiary structures using evolutionary information. This webserver will operate behind the scenes as a suite of tools (the outputs of which will be available for interested users), from homologous sequences retrieval to evaluation of the resulting model. First, this tool will automatically retrieve and align homologous sequences using existing and novel algorithms. This aim will search for relevant homologs to any single sequence entered as input, which represents an unmet challenge for most current programs. Second, the application using covariation analysis will address the likeliness that the input RNA sequence has a conserved structure, so not every sequence used as input will necessarily output a structure model. Subsequent modules in the online tool will evaluate the quality of the alignment, and possibly improve this alignment, so that a model with a confidence score could be proposed. Regardless of the outcome, the user will have a result that will take into account evolutionary as well as up-to-date RNA structural information, so it will not be biased by the use of a single set of parameters, as is often the case with existing predictive methods. A more holistic and straightforward computational tool harnessing evolutionary information will help disseminate the use of those methods to the larger RNA biology community, for maximum impact on experimental design in RNA research.