RNAiFold2T：热IRES开关的约束规划设计
RNAiFold2T: Constraint Programming design of thermo-IRES switches
摘要：
动机：RNA温度计（RNAT）是顺式调节元件，在温度变化时改变二级结构。RNATs通常参与热休克、冷休克和毒力基因的调控，是合成生物学中一个有趣的潜在资源，其中工程化RNATs可能被证明是生物传感器和条件基因调控的有用工具。结果：解决2温度逆折叠问题是RNAT工程的关键。在这里，我们介绍RNAiFold 2 T，第一个约束编程（CP）和大邻域搜索（LNS）算法来解决这个问题。RNAiFold 2 T对现有程序（自适应行走和遗传算法）逆折叠的基准测试表明，我们的软件生成两个数量级以上的解决方案，从而允许- ING充分探索的解决方案的空间。随后，解决方案可以优先计算各种措施，包括概率的目标结构中的合奏，熔化温度等。使用这种策略，我们合理地设计了两个热敏内部核糖体进入位点（热IRES）的元素，其归一化帽独立transla-灰效率约50%以上，在42？C、30？C，当在网织红细胞裂解物中检测时。翻译效率低于野生型IRES元件的翻译效率，另一方面，野生型IRES元件完全耐温度升高。这似乎是第一个纯计算设计的功能RNA温控开关，当然也是第一个纯计算设计的功能thermo-IRES元件。可用性：RNAiFold 2 T作为新发布的RNAiFold3.0的一部分在https://github.com/clotelab/RNAiFold和http：//bioinformatics.bc.edu/clotelab/RNAiFold公开可用，后者也具有网络服务器。该软件是用C++编写的，并使用OR-Tools CP搜索引擎。
英文摘要：
Motivation: RNA thermometers (RNATs) are cis-regulatory ele- ments that change secondary structure upon temperature shift. Often involved in the regulation of heat shock, cold shock and virulence genes, RNATs constitute an interesting potential resource in synthetic biology, where engineered RNATs could prove to be useful tools in biosensors and conditional gene regulation. Results: Solving the 2-temperature inverse folding problem is critical for RNAT engineering. Here we introduce RNAiFold2T, the first Constraint Programming (CP) and Large Neighborhood Search (LNS) algorithms to solve this problem. Benchmarking tests of RNAiFold2T against existent programs (adaptive walk and genetic algorithm) inverse folding show that our software generates two orders of magnitude more solutions, thus allow- ing ample exploration of the space of solutions. Subsequently, solutions can be prioritized by computing various measures, including probability of target structure in the ensemble, melting temperature, etc. Using this strategy, we rationally designed two thermosensor internal ribosome entry site (thermo-IRES) elements, whose normalized cap-independent transla- tion efficiency is approximately 50% greater at 42?C than 30?C, when tested in reticulocyte lysates. Translation efficiency is lower than that of the wild-type IRES element, which on the other hand is fully resistant to temperature shift-up. This appears to be the first purely computational design of functional RNA thermoswitches, and certainly the first purely computational design of functional thermo-IRES elements. Availability: RNAiFold2T is publicly available as as part of the new re- lease RNAiFold3.0 at https://github.com/clotelab/RNAiFold and http: //bioinformatics.bc.edu/clotelab/RNAiFold, which latter has a web server as well. The software is written in C++ and uses OR-Tools CP search engine.
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