In vitro RNA random pools are not structurally diverse: A computational analysis

Gevertz, Jana L.; Gan, Hin Hark; Schlick, Tamar

doi:10.1261/rna.7271405

Cited by 80 publications

(100 citation statements)

References 46 publications

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“…Stem P1 anchors the other side of the recognition bulge. Both empirical findings (Davis and Szostak 2002;Carothers et al 2004) and theoretical considerations (Gevertz et al 2005) argue that designing additional secondary structure elements into sequence libraries may further increase the likelihood of obtaining highly-active molecules.…”

Section: Discussionmentioning

confidence: 99%

Solution structure of an informationally complex high-affinity RNA aptamer to GTP

Carothers¹,

Davis²,

Chou³

et al. 2006

RNA

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Higher-affinity RNA aptamers to GTP are more informationally complex than lower-affinity aptamers. Analog binding studies have shown that the additional information needed to improve affinity does not specify more interactions with the ligand. In light of those observations, we would like to understand the structural characteristics that enable complex aptamers to bind their ligands with higher affinity. Here we present the solution structure of the 41-nt Class I GTP aptamer (K d = 75 nM) as determined by NMR. The backbone of the aptamer forms a reverse-S that shapes the binding pocket. The ligand nucleobase stacks between purine platforms and makes hydrogen bonds with the edge of another base. Interestingly, the local modes of interaction for the Class I aptamer and an RNA aptamer that binds ATP with a K d of 6 mM are very much alike. The aptamers exhibit nearly identical levels of binding specificity and fraction of ligand sequestered from the solvent (81%-85%). However, the GTP aptamer is more informationally complex ($45 vs. 35 bits) and has a larger recognition bulge (15 vs. 12 nucleotides) with many more stabilizing base-base interactions. Because the aptamers have similar modes of ligand binding, we conclude that the stabilizing structural elements in the Class I aptamer are responsible for much of the difference in K d . These results are consistent with the hypothesis that increasing the number of intra-RNA interactions, rather than adding specific contacts to the ligand, is the simplest way to improve binding affinity.

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Section: Discussionmentioning

confidence: 99%

Solution structure of an informationally complex high-affinity RNA aptamer to GTP

Carothers¹,

Davis²,

Chou³

et al. 2006

RNA

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show abstract

“…More relevant is the repertoire of RNA secondary structures, the precursors of chemical function, originated in a pool of random sequences. Insights into the distribution of structural motifs can be obtained from theoretical studies (Fontana et al 1993;Knight and Yarus 2003;Gevertz et al 2005) and from analyses of the repertoire of secondary structures present in extant RNA molecules (Bourdeau et al 1999;Hendrix et al 2005).…”

Section: A Stepwise Model For the Origin Of The Rna Worldmentioning

confidence: 99%

The dawn of the RNA World: Toward functional complexity through ligation of random RNA oligomers

Briones¹,

Stich²,

Manrubia³

2009

RNA

100

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A main unsolved problem in the RNA World scenario for the origin of life is how a template-dependent RNA polymerase ribozyme emerged from short RNA oligomers obtained by random polymerization on mineral surfaces. A number of computational studies have shown that the structural repertoire yielded by that process is dominated by topologically simple structures, notably hairpin-like ones. A fraction of these could display RNA ligase activity and catalyze the assembly of larger, eventually functional RNA molecules retaining their previous modular structure: molecular complexity increases but template replication is absent. This allows us to build up a stepwise model of ligation-based, modular evolution that could pave the way to the emergence of a ribozyme with RNA replicase activity, step at which information-driven Darwinian evolution would be triggered.

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“…In SELEX experiments, aimed to produce aptamers with a certain function and hence structure, both the size of the pool and the length of the molecules are important issues in determining the outcome of the selection process, as experimental and theoretical work has shown (Bartel and Szostak, 1993;Sabeti et al, 1997;Gevertz et al, 2005). Furthermore, the structural repertoire of the pool strongly depends on its nucleotide composition (Knight et al, 2005;Kim et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Motif frequency and evolutionary search times in RNA populations

Stich

Manrubia

2011

Journal of Theoretical Biology

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RNA molecules, through their dual identity as sequence and structure, are an appropriate experimental and theoretical model to study the genotype-phenotype map and evolutionary processes taking place in simple replicator populations. In this computational study, we relate properties of the sequence-structure map, in particular the abundance of a given secondary structure in a random pool, with the number of replicative events that an initially random population of sequences needs to find that structure through mutation and selection. For common structures, this search process turns out to be much faster than for rare structures. Furthermore, search and fixation processes are more efficient in a wider range of mutation rates for common structures, thus indicating that evolvability of RNA populations is not simply determined by abundance. We also find significant differences in the search and fixation processes for structures of same abundance, and relate them with the number of base pairs forming the structure. Moreover, the influence of the nucleotide content of the RNA sequences on the search process is studied. Our results advance in the understanding of the distribution and attainability of RNA secondary structures. They hint at the fact that, beyond sequence length and sequence-to-function redundancy, the mutation rate that permits localization and fixation of a given phenotype strongly depends on its relative abundance and global, in general nonuniform, distribution in sequence space.

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In vitro RNA random pools are not structurally diverse: A computational analysis

Cited by 80 publications

References 46 publications

Solution structure of an informationally complex high-affinity RNA aptamer to GTP

Solution structure of an informationally complex high-affinity RNA aptamer to GTP

The dawn of the RNA World: Toward functional complexity through ligation of random RNA oligomers

Motif frequency and evolutionary search times in RNA populations

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