23,130 research outputs found
Designing RNA secondary structures is hard
An RNA sequence is a word over an alphabet on four elements {A, C, G, U} called bases. RNA sequences fold into secondary structures where some bases match one another while others remain unpaired. Pseudoknot-free secondary structures can be represented as well-parenthesized expressions with additional dots, where pairs of matching parentheses symbolize paired bases and dots, unpaired bases. The two fundamental problems in RNA algorithmic are to predict how sequences fold within some model of energy and to design sequences of bases which will fold into targeted secondary structures. Predicting how a given RNA sequence folds into a pseudoknot-free secondary structure is known to be solvable in cubic time since the eighties and in truly subcubic time by a recent result of Bringmann et al. (FOCS 2016), whereas Lyngsø has shown it is NP-complete if pseudoknots are allowed (ICALP 2004). As a stark contrast, it is unknown whether or not designing a given RNA secondary structure is a tractable task; this has been raised as a challenging open question by Anne Condon (ICALP 2003). Because of its crucial importance in a number of fields such as pharmaceutical research and biochemistry, there are dozens of heuristics and software libraries dedicated to RNA secondary structure design. It is therefore rather surprising that the computational complexity of this central problem in bioinformatics has been unsettled for decades.
In this paper we show that, in the simplest model of energy which is the Watson-Crick model the design of secondary structures is NP-complete if one adds natural constraints of the form: index i of the sequence has to be labeled by base b. This negative result suggests that the same lower bound holds for more realistic models of energy. It is noteworthy that the additional constraints are by no means artificial: they are provided by all the RNA design pieces of software and they do correspond to the actual practice (see for example the instances of the EteRNA project). Our reduction from a variant of 3-Sat has as main ingredients: arches of parentheses of different widths, a linear order interleaving variables and clauses, and an intended rematching strategy which increases the number of pairs iff the three literals of a same clause are not satisfied. The correctness of the construction is also quite intricate; it relies on the polynomial algorithm for the design of saturated structures – secondary structures without dots – by Haleš et al. (Algorithmica 2016), counting arguments, and a concise case analysis
Designing RNA secondary structures is hard
An RNA sequence is a word over an alphabet on four elements {A, C, G, U} called bases. RNA sequences fold into secondary structures where some bases match one another while others remain unpaired. Pseudoknot-free secondary structures can be represented as well-parenthesized expressions with additional dots, where pairs of matching parentheses symbolize paired bases and dots, unpaired bases. The two fundamental problems in RNA algorithmic are to predict how sequences fold within some model of energy and to design sequences of bases which will fold into targeted secondary structures. Predicting how a given RNA sequence folds into a pseudoknot-free secondary structure is known to be solvable in cubic time since the eighties and in truly subcubic time by a recent result of Bringmann et al. (FOCS 2016), whereas Lyngsø has shown it is NP-complete if pseudoknots are allowed (ICALP 2004). As a stark contrast, it is unknown whether or not designing a given RNA secondary structure is a tractable task; this has been raised as a challenging open question by Anne Condon (ICALP 2003). Because of its crucial importance in a number of fields such as pharmaceutical research and biochemistry, there are dozens of heuristics and software libraries dedicated to RNA secondary structure design. It is therefore rather surprising that the computational complexity of this central problem in bioinformatics has been unsettled for decades.
In this paper we show that, in the simplest model of energy which is the Watson-Crick model the design of secondary structures is NP-complete if one adds natural constraints of the form: index i of the sequence has to be labeled by base b. This negative result suggests that the same lower bound holds for more realistic models of energy. It is noteworthy that the additional constraints are by no means artificial: they are provided by all the RNA design pieces of software and they do correspond to the actual practice (see for example the instances of the EteRNA project). Our reduction from a variant of 3-Sat has as main ingredients: arches of parentheses of different widths, a linear order interleaving variables and clauses, and an intended rematching strategy which increases the number of pairs iff the three literals of a same clause are not satisfied. The correctness of the construction is also quite intricate; it relies on the polynomial algorithm for the design of saturated structures – secondary structures without dots – by Haleš et al. (Algorithmica 2016), counting arguments, and a concise case analysis
Designing RNA Secondary Structures is Hard
International audienceAn RNA sequence is a word over an alphabet on four elements {A, C, G, U } called bases. RNA sequences fold into secondary structures where some bases pair with one another while others remain unpaired. Pseudoknot-free secondary structures can be represented as well-parenthesized expressions with additional dots, where pairs of matching parentheses symbolize paired bases and dots, unpaired bases. The two fundamental problems in RNA algorithmic are to predict how sequences fold within some model of energy and to design sequences of bases which will fold into targeted secondary structures. Predicting how a given RNA sequence folds into a pseudoknot-free secondary structure is known to be solvable in cubic time since the eighties and in truly subcubic time by a recent result of Bringmann et al. (FOCS 2016), whereas Lyngsø has shown it is NP-complete if pseudoknots are allowed (ICALP 2004). As a stark contrast, it is unknown whether or not designing a given RNA secondary structure is a tractable task; this has been raised as a challenging open question by Anne Condon (ICALP 2003). Because of its crucial importance in a number of fields such as pharmaceutical research and biochemistry, there are dozens of heuristics and software libraries dedicated to RNA secondary structure design. It is therefore rather surprising that the computational complexity of this central problem in bioinformatics has been unsettled for decades. In this paper we show that, in the simplest model of energy which is the Watson-Crick model the design of secondary structures is NP-complete if one adds natural constraints of the form: index i of the sequence has to be labeled by base b. This negative result suggests that the same lower bound holds for more realistic models of energy. It is noteworthy that the additional constraints are by no means artificial: they are provided by all the RNA design pieces of software and they do correspond to the actual practice (see for example the instances of the EteRNA project). Our reduction from a variant of 3-Sat has as main ingredients: arches of parentheses of different widths, a linear order interleaving variables and clauses, and an intended rematching strategy which increases the number of pairs iff the three literals of a same clause are false. The correctness of the construction is also quite intricate; it relies on the polynomial algorithm for the design of saturated structures-secondary structures without dots-by Haleš et al. (Algorithmica 2016), counting arguments, and a concise case analysis
Flexible RNA design under structure and sequence constraints using formal languages
The problem of RNA secondary structure design (also called inverse folding)
is the following: given a target secondary structure, one aims to create a
sequence that folds into, or is compatible with, a given structure. In several
practical applications in biology, additional constraints must be taken into
account, such as the presence/absence of regulatory motifs, either at a
specific location or anywhere in the sequence. In this study, we investigate
the design of RNA sequences from their targeted secondary structure, given
these additional sequence constraints. To this purpose, we develop a general
framework based on concepts of language theory, namely context-free grammars
and finite automata. We efficiently combine a comprehensive set of constraints
into a unifying context-free grammar of moderate size. From there, we use
generic generic algorithms to perform a (weighted) random generation, or an
exhaustive enumeration, of candidate sequences. The resulting method, whose
complexity scales linearly with the length of the RNA, was implemented as a
standalone program. The resulting software was embedded into a publicly
available dedicated web server. The applicability demonstrated of the method on
a concrete case study dedicated to Exon Splicing Enhancers, in which our
approach was successfully used in the design of \emph{in vitro} experiments.Comment: ACM BCB 2013 - ACM Conference on Bioinformatics, Computational
Biology and Biomedical Informatics (2013
RNAiFold2T: Constraint Programming design of thermo-IRES switches
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.Comment: 24 pages, 5 figures, Intelligent Systems for Molecular Biology (ISMB
2016), to appear in journal Bioinformatics 201
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