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Fixed-parameter tractable sampling for RNA design with multiple target structures.

ABSTRACT: BACKGROUND:The design of multi-stable RNA molecules has important applications in biology, medicine, and biotechnology. Synthetic design approaches profit strongly from effective in-silico methods, which substantially reduce the need for costly wet-lab experiments. RESULTS:We devise a novel approach to a central ingredient of most in-silico design methods: the generation of sequences that fold well into multiple target structures. Based on constraint networks, our approach supports generic Boltzmann-weighted sampling, which enables the positive design of RNA sequences with specific free energies (for each of multiple, possibly pseudoknotted, target structures) and GC-content. Moreover, we study general properties of our approach empirically and generate biologically relevant multi-target Boltzmann-weighted designs for an established design benchmark. Our results demonstrate the efficacy and feasibility of the method in practice as well as the benefits of Boltzmann sampling over the previously best multi-target sampling strategy-even for the case of negative design of multi-stable RNAs. Besides empirically studies, we finally justify the algorithmic details due to a fundamental theoretic result about multi-stable RNA design, namely the #P-hardness of the counting of designs. CONCLUSION:introduces a novel, flexible, and effective approach to multi-target RNA design, which promises broad applicability and extensibility. Our free software is available at: https://github.com/yannponty/RNARedPrint Supplementary data are available online.

SUBMITTER: Hammer S

PROVIDER: S-EPMC6482512 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Fixed-parameter tractable sampling for RNA design with multiple target structures.

Hammer Stefan S Wang Wei W Will Sebastian S Ponty Yann Y

BMC bioinformatics 20190425 1

<h4>Background</h4>The design of multi-stable RNA molecules has important applications in biology, medicine, and biotechnology. Synthetic design approaches profit strongly from effective in-silico methods, which substantially reduce the need for costly wet-lab experiments.<h4>Results</h4>We devise a novel approach to a central ingredient of most in-silico design methods: the generation of sequences that fold well into multiple target structures. Based on constraint networks, our approach support ...[more]

PMID: 31023239

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Project description:BackgroundRNAs are attractive molecules as the biological parts for synthetic biology. In particular, the ability of conformational changes, which can be encoded in designer RNAs, enables us to create multistable molecular switches that function in biological circuits. Although various algorithms for designing such RNA switches have been proposed, the previous algorithms optimize the RNA sequences against the weighted sum of objective functions, where empirical weights among objective functions are used. In addition, an RNA design algorithm for multiple pseudoknot targets is currently not available.ResultsWe developed a novel computational tool for automatically designing RNA sequences which fold into multiple target secondary structures. Our algorithm designs RNA sequences based on multi-objective genetic algorithm, by which we can explore the RNA sequences having good objective function values without empirical weight parameters among the objective functions. Our algorithm has great flexibility by virtue of this weight-free nature. We benchmarked our multi-target RNA design algorithm with the datasets of two, three, and four target structures and found that our algorithm shows better or comparable design performances compared with the previous algorithms, RNAdesign and Frnakenstein. In addition to the benchmarks with pseudoknot-free datasets, we benchmarked MODENA with two-target pseudoknot datasets and found that MODENA can design the RNAs which have the target pseudoknotted secondary structures whose free energies are close to the lowest free energy. Moreover, we applied our algorithm to a ribozyme-based ON-switch which takes a ribozyme-inactive secondary structure when the theophylline aptamer structure is assumed.ConclusionsCurrently, MODENA is the only RNA design software which can be applied to multiple pseudoknot targets. Successful design results for the multiple targets and an RNA device indicate usefulness of our multi-objective RNA design algorithm.

Project description:MOTIVATION: Thermodynamics-based dynamic programming RNA secondary structure algorithms have been of immense importance in molecular biology, where applications range from the detection of novel selenoproteins using expressed sequence tag (EST) data, to the determination of microRNA genes and their targets. Dynamic programming algorithms have been developed to compute the minimum free energy secondary structure and partition function of a given RNA sequence, the minimum free-energy and partition function for the hybridization of two RNA molecules, etc. However, the applicability of dynamic programming methods depends on disallowing certain types of interactions (pseudoknots, zig-zags, etc.), as their inclusion renders structure prediction an nondeterministic polynomial time (NP)-complete problem. Nevertheless, such interactions have been observed in X-ray structures. RESULTS: A non-Boltzmannian Monte Carlo algorithm was designed by Wang and Landau to estimate the density of states for complex systems, such as the Ising model, that exhibit a phase transition. In this article, we apply the Wang-Landau (WL) method to compute the density of states for secondary structures of a given RNA sequence, and for hybridizations of two RNA sequences. Our method is shown to be much faster than existent software, such as RNAsubopt. From density of states, we compute the partition function over all secondary structures and over all pseudoknot-free hybridizations. The advantage of the WL method is that by adding a function to evaluate the free energy of arbitrary pseudoknotted structures and of arbitrary hybridizations, we can estimate thermodynamic parameters for situations known to be NP-complete. This extension to pseudoknots will be made in the sequel to this article; in contrast, the current article describes the WL algorithm applied to pseudoknot-free secondary structures and hybridizations. AVAILABILITY: The WL RNA hybridization web server is under construction at http://bioinformatics.bc.edu/clotelab/.

Project description:To deliver more therapeutics to more patients more quickly and economically is the ultimate goal of pharmaceutical researchers. The advent and rapid development of artificial intelligence (AI), in combination with other powerful computational methods in drug discovery, makes this goal more practical than ever before. Here, we describe a new strategy, retro drug design, or RDD, to create novel small-molecule drugs from scratch to meet multiple predefined requirements, including biological activity against a drug target and optimal range of physicochemical and ADMET properties. The molecular structure was represented by an atom typing based molecular descriptor system, optATP, which was further transformed to the space of loading vectors from principal component analysis. Traditional predictive models were trained over experimental data for the target properties using optATP and shallow machine learning methods. The Monte Carlo sampling algorithm was then utilized to find the solutions in the space of loading vectors that have the target properties. Finally, a deep learning model was employed to decode molecular structures from the solutions. To test the feasibility of the algorithm, we challenged RDD to generate novel kinase inhibitors from random numbers with five different ADMET properties optimized at the same time. The best Tanimoto similarity score between the generated valid structures and the available 4,314 kinase inhibitors was < 0.50, indicating a high extent of novelty of the generated compounds. From the 3,040 structures that met all six target properties, 20 were selected for synthesis and experimental measurement of inhibition activity over 97 representative kinases and the ADMET properties. Fifteen and eight compounds were determined to be hits or strong hits, respectively. Five of the six strong kinase inhibitors have excellent experimental ADMET properties. The results presented in this paper illustrate that RDD has the potential to significantly improve the current drug discovery process.

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Fixed-parameter tractable sampling for RNA design with multiple target structures.

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Fixed-parameter tractable sampling for RNA design with multiple target structures.

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