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1. RNA fold prediction by Monte Carlo in graph space and the statistical mechanics of tertiary interactions

   https://doi.org/10.1261/rna.080216.124  

   Phan, Ethan NH; Mak, Chi H (December 2024, RNA)

   Using a graph representation of RNA structures, we have studied the ensembles of secondary and tertiary graphs of two sets of RNA with Monte Carlo simulations. The first consisted of 91 target ribozyme and riboswitch sequences of moderate lengths (<150 nt) having a variety of secondary, H-type pseudoknots and kissing loop interactions. The second set consisted of 71 more diverse sequences across many RNA families. Using a simple empirical energy model for tertiary interactions and only sequence information for each target as input, the simulations examined how tertiary interactions impact the statistical mechanics of the fold ensembles. The results show that the graphs proliferate enormously when tertiary interactions are possible, producing an entropic driving force for the ensemble to access folds having tertiary structures even though they are overall energetically unfavorable in the energy model. For each of the targets in the two test sets, we assessed the quality of the model and the simulations by examining how well the simulated structures were able to predict the native fold, and compared the results to fold predictions from ViennaRNA. Our model generated good or excellent predictions in a large majority of the targets. Overall, this method was able to produce predictions of comparable quality to Vienna, but it outperformed Vienna for structures with H-type pseudoknots. The results suggest that while tertiary interactions are predicated on real-space contacts, their impacts on the folded structure of RNA can be captured by graph space information for sequences of moderate lengths, using a simple tertiary energy model for the loops, the base pairs, and base stacks. 

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2. A unified Watson-Crick geometry drives transcription of six-letter expanded DNA alphabets by E. coli RNA polymerase

   https://doi.org/10.1038/s41467-023-43735-9  

   Oh, Juntaek; Shan, Zelin; Hoshika, Shuichi; Xu, Jun; Chong, Jenny; Benner, Steven A.; Lyumkis, Dmitry; Wang, Dong (December 2023, Nature Communications)

   Abstract Artificially Expanded Genetic Information Systems (AEGIS) add independently replicable unnatural nucleotide pairs to the natural G:C and A:T/U pairs found in native DNA, joining the unnatural pairs through alternative modes of hydrogen bonding. Whether and how AEGIS pairs are recognized and processed by multi-subunit cellular RNA polymerases (RNAPs) remains unknown. Here, we show thatE. coliRNAP selectively recognizes unnatural nucleobases in a six-letter expanded genetic system. High-resolution cryo-EM structures of three RNAP elongation complexes containing template-substrate UBPs reveal the shared principles behind the recognition of AEGIS and natural base pairs. In these structures, RNAPs are captured in an active state, poised to perform the chemistry step. At this point, the unnatural base pair adopts a Watson-Crick geometry, and the trigger loop is folded into an active conformation, indicating that the mechanistic principles underlying recognition and incorporation of natural base pairs also apply to AEGIS unnatural base pairs. These data validate the design philosophy of AEGIS unnatural basepairs. Further, we provide structural evidence supporting a long-standing hypothesis that pair mismatch during transcription occurs via tautomerization. Together, our work highlights the importance of Watson-Crick complementarity underlying the design principles of AEGIS base pair recognition. 

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3. Challenges with Simulating Modified RNA: Insights into Role and Reciprocity of Experimental and Computational Approaches

   https://doi.org/10.3390/genes13030540  

   D’Esposito, Rebecca J.; Myers, Christopher A.; Chen, Alan A.; Vangaveti, Sweta (March 2022, Genes)

   RNA is critical to a broad spectrum of biological and viral processes. This functional diversity is a result of their dynamic nature; the variety of three-dimensional structures that they can fold into; and a host of post-transcriptional chemical modifications. While there are many experimental techniques to study the structural dynamics of biomolecules, molecular dynamics simulations (MDS) play a significant role in complementing experimental data and providing mechanistic insights. The accuracy of the results obtained from MDS is determined by the underlying physical models i.e., the force-fields, that steer the simulations. Though RNA force-fields have received a lot of attention in the last decade, they still lag compared to their protein counterparts. The chemical diversity imparted by the RNA modifications adds another layer of complexity to an already challenging problem. Insight into the effect of RNA modifications upon RNA folding and dynamics is lacking due to the insufficiency or absence of relevant experimental data. This review provides an overview of the state of MDS of modified RNA, focusing on the challenges in parameterization of RNA modifications as well as insights into relevant reference experiments necessary for their calibration. 

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4. RNA multimerization as an organizing force for liquid–liquid phase separation

   https://doi.org/10.1261/rna.078999.121  

   Bevilacqua, Philip C.; Williams, Allison M.; Chou, Hong-Li; Assmann, Sarah M. (December 2021, RNA)

   RNA interactions are exceptionally strong and highly redundant. As such, nearly any two RNAs have the potential to interact with one another over relatively short stretches, especially at high RNA concentrations. This is especially true for pairs of RNAs that do not form strong self-structure. Such phenomena can drive liquid–liquid phase separation, either solely from RNA–RNA interactions in the presence of divalent or organic cations, or in concert with proteins. RNA interactions can drive multimerization of RNA strands via both base-pairing and tertiary interactions. In this article, we explore the tendency of RNA to form stable monomers, dimers, and higher order structures as a function of RNA length and sequence through a focus on the intrinsic thermodynamic, kinetic, and structural properties of RNA. The principles we discuss are independent of any specific type of biomolecular condensate, and thus widely applicable. We also speculate how external conditions experienced by living organisms can influence the formation of nonmembranous compartments, again focusing on the physical and structural properties of RNA. Plants, in particular, are subject to diverse abiotic stresses including extreme temperatures, drought, and salinity. These stresses and the cellular responses to them, including changes in the concentrations of small molecules such as polyamines, salts, and compatible solutes, have the potential to regulate condensate formation by melting or strengthening base-pairing. Reversible condensate formation, perhaps including regulation by circadian rhythms, could impact biological processes in plants, and other organisms. 

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5. Fluid-mediated deformation leads to weakening, strengthening, and block-in-matrix structures during prograde subduction mélange formation

   https://doi.org/10.1130/G53323.1  

   Condit, Cailey B; Poulaki, Eirini M; Lindquist, Peter C; Nichols, Claire IO; Ferrell, Megan E; Odlum, Margo L; Hoover, William F; Guevara, Victor E (August 2025, Geology)

   Mélange (or block-in-matrix structures) exerts a first-order control on both the mechanical and chemical evolution of subduction megathrusts. However, the timing and mechanisms that form mélanges are variable and debated. Field observations and (micro-) structural analyses from a metasedimentary mélange in the lawsonite blueschist unit of the Catalina Schist (Santa Catalina Island, California, USA) reveal that syn-subduction deformation and fluid-mediated processes led to mélange formation at the plate interface. Deposited as turbidites, early shear occurred parallel to bedding planes (S1 foliation). At near peak subduction conditions, at the base of the subduction seismogenic zone (∼1.0 GPa, 320 °C), the rocks were intensely deformed in recumbent open to tight folds (F2) with axial planar cleavages (S2). Fracturing, fluid flow, and quartz precipitation are preserved as extensional vein mesh networks in fold noses. Continued shearing led to boudinage of these strengthened noses and transformation into strong blocks within the weaker less-veined matrix composed of high-strain fold limbs (S1−2). Microstructures reveal viscous deformation in the high-strain fold limbs occurred by pressure-solution creep of fine-grained quartz ± albite. In contrast, the fold noses and/or blocks contain coarse-grained quartz veins with little evidence of deformation. These rocks record the development of syn-subduction block-in-matrix mélange structures through the interaction of deformation and mineral precipitation; pressure solution weakened fold limbs-turned-matrix and veining strengthened fold noses-turned-blocks. Although mélange structure is often invoked to explain tremor and slow slip, rheological analysis indicates that these metasedimentary rocks can host tectonic creeping but cannot accommodate slow-slip strain rates by the deformation mechanisms preserved in their microstructures. 

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