Toward a Molecular Mechanism of Complementary RNA Duplexes Denaturation

RNAduplexes are relatively rare but play very important biologicalroles. As an end-product of template-based RNA replication, they alsohave key implications for hypothetical primitive forms of life. Unlessthey are specifically separated by enzymes, these duplexes denatureupon a temperature increase. However, mechanistic and kinetic aspectsof RNA (and DNA) duplex thermal denaturation remain unclear at themicroscopic level. We propose an in silico strategythat probes the thermal denaturation of RNA duplexes and allows foran extensive conformational space exploration along a wide temperaturerange with atomistic precision. We show that this approach first accountsfor the strong sequence and length dependence of the duplexes meltingtemperature, reproducing the trends seen in the experiments and predictedby nearest-neighbor models. The simulations are then instrumentalat providing a molecular picture of the temperature-induced strandseparation. The textbook canonical all-or-nothingtwo-state model, very much inspired by the protein folding mechanism,can be nuanced. We demonstrate that a temperature increase leads tosignificantly distorted but stable structures with extensive base-frayingat the extremities, and that the fully formed duplexes typically donot form around melting. The duplex separation therefore appears asmuch more gradual than commonly thought.

Automated summary

RNAduplexes are rare but have important biological roles. They are end-products of template-based RNA replication and have implications for primitive forms of life. The mechanism of RNA (and DNA) duplex thermal denaturation is not well understood.