Salt dependent mesoscopic model for RNA at multiple strand concentrations

Ferreira, Izabela; Amarante, Tauanne Dias; Weber, Gerald

doi:10.1016/j.bpc.2021.106551

Cited by 4 publications

(3 citation statements)

References 75 publications

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“…However, reports have been made, both from experimental studies [22][23][24] as well as from theoretical considerations (some based on nearestneighbor models themselves), 15,20,21 of significant deviations from a two-state model for RNA duplexes (de)hybridization, with base fraying at the duplex extremities [25][26][27][28][29][30][31] and the presence of stable intermediates. 32,33 Similar observations were made, and were actually much better characterized, for DNA duplexes.…”

Section: Introductionmentioning

confidence: 99%

Atomistic simulations of RNA duplex thermal denaturation: sequence- and forcefield-dependence

Dabin,

Stirnemann

2023

Preprint

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Double-stranded RNA is the end-product of template-based replication, and is also the functional state of some biological RNAs. Similarly to proteins and DNA, they can be denatured by temperature, with important physiological and technological implications. Here, we use anin silicostrategy to probe the thermal denaturation of RNA duplexes. Following previous results that were obtained on a few different duplexes, and which nuanced the canonical 2-state picture of nucleic acid denaturation, we here specifically address three different aspects that improve our description of the temperature-induced dsRNA separation. First, we investigate the effect of the spatial distribution of weak and strong base-pairs among the duplex sequence. We show that the deviations from the two-state dehybridization mechanism are more pronounced when a strong core is flanked with weak extremities, while duplexes with a weak core but strong extremities exhibit a two-state behavior, which can be explained by the key role played by base fraying. This was later verified by generating artificial hairpin or circular states containing one or two locked duplex extremities, which results in an important reinforcement of the entire HB structure of the duplex and higher melting temperatures. Finally, we demonstrate that our results are little sensitive to the employed combination of RNA and water forcefields. The trends in thermal stability among the different sequences as well as the observed unfolding mechanisms (and the deviations from a two-state scenario) remain the same regardless of the employed atomistic models. However, our study points to possible limitations of recent reparametrizations of the Amber RNA forcefield, which sometimes results in duplexes that readily denature under ambient conditions, in contradiction with available experimental results.

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Section: Introductionmentioning

confidence: 99%

Atomistic simulations of RNA duplex thermal denaturation: sequence- and forcefield-dependence

Dabin,

Stirnemann

2023

Preprint

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“…The model included locked nucleic acid (LNA) enriched probes that were designed specifically to target the desired DNA and RNA. LNA is a nucleic acid analogue which improves the probes' affinity and specificity especially for DNA:RNA recognition [24,29,[32][33][34]. Using this model, we optimized oligonucleotide reagents so that the target SNP in coding RNA was discriminated with high specificity [31].…”

Section: Introductionmentioning

confidence: 99%

Mutations in microRNA-128-2-3p identified with amplification-free hybridization assay

Slott,

Krüger-Jensen,

Ferreira da Silva

et al. 2023

PLoS ONE

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We describe a quantitative detection method for mutated microRNA in human plasma samples. Specific oligonucleotides designed from a Peyrard-Bishop model allowed accurate prediction of target:probe recognition affinity and specificity. Our amplification-free tandem bead-based hybridization assay had limit of detection of 2.2 pM. Thereby, the assay allowed identification of single-nucleotide polymorphism mismatch profiles in clinically relevant microRNA-128-2-3p, showing terminal mutations that correlate positively with inflammatory colitis and colorectal cancer.

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“…On the other hand, mesoscopic models make use of the same melting temperature data as NN models, but have the potential to provide insights into the hydrogen bonds and stacking interactions . We have shown that it is possible to obtain a good insight into these interactions from melting temperatures, and we have validated the method over the past 10 years for a variety of different oligonucleotides, such as RNA, , DNA mismatches, and DNA analogues such as TNA . A recent study by our group, using this type of mesoscopic modeling, found that the increased stability of LNA is largely hydrogen-bond-driven.…”

Section: Introductionmentioning

confidence: 99%

Complete Mesoscopic Parameterization of Single LNA Modifications in DNA Applied to Oncogene Probe Design

Ferreira

Slott

Astakhova

et al. 2021

J. Chem. Inf. Model.

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The use of mesoscopic models to describe the thermodynamic properties of locked nucleic acid (LNA)-modified nucleotides can provide useful insights into their properties, such as hydrogen-bonding and stacking interactions. In addition, the mesoscopic parameters can be used to optimize LNA insertion in probes, to achieve accurate melting temperature predictions, and to obtain duplex opening profiles at the base-pair level. Here, we applied this type of model to parameterize a large set of melting temperatures for LNA-modified sequences, from published sources, covering all possible nearest-neighbor configurations. We have found a very large increase in Morse potentials, which indicates very strong hydrogen bonding as the main cause of improved LNA thermodynamic stability. LNA-modified adenine−thymine (AT) was found to have similar hydrogen bonding to unmodified cytosine−guanine (CG) base pairs, while for LNA CG, we found exceptionally large hydrogen bonding. In contrast, stacking interactions, which were thought to be behind the stability of LNA, were similar to unmodified DNA in most cases. We applied the new LNA parameters to the design of BRAF, KRAS, and EGFR oncogene variants by testing all possible LNA modifications. Selected sequences were then synthesized and had their hybridization temperatures measured, achieving a prediction accuracy within 1 °C. We performed a detailed base-pair opening analysis to discuss specific aspects of these probe hybridizations that may be relevant for probe design.

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Salt dependent mesoscopic model for RNA at multiple strand concentrations

Cited by 4 publications

References 75 publications

Atomistic simulations of RNA duplex thermal denaturation: sequence- and forcefield-dependence

Atomistic simulations of RNA duplex thermal denaturation: sequence- and forcefield-dependence

Mutations in microRNA-128-2-3p identified with amplification-free hybridization assay

Complete Mesoscopic Parameterization of Single LNA Modifications in DNA Applied to Oncogene Probe Design

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