Abstract
For the last 20 years, it has been common lore that the free energy of RNA duplexes formed from canonical Watson–Crick base pairs (bps) can be largely approximated with dinucleotide bp parameters and a few simple corrective constants that are duplex independent. Additionally, the standard benchmark set of duplexes used to generate the parameters were GC-rich in the shorter duplexes and AU-rich in the longer duplexes, and the length of the majority of the duplexes ranged between 6 and 8 bps. We were curious if other models would generate similar results and whether adding longer duplexes of 17 bps would affect the conclusions. We developed a gradient-descent fitting program for obtaining free-energy parameters—the changes in Gibbs free energy (ΔG), enthalpy (ΔH), and entropy (ΔS), and the melting temperature (Tm)—directly from the experimental melting curves. Using gradient descent and a genetic algorithm, the duplex melting results were combined with the standard benchmark data to obtain bp parameters. Both the standard (Turner) model and a new model that includes length-dependent terms were tested. Both models could fit the standard benchmark data; however, the new model could handle longer sequences better. We developed an updated strategy for fitting the duplex melting data.
Highlights
In RNA structure, a stem is a segment of double-stranded RNA forming a duplex that is typically 3 to 10 bps long
It is the primary information extracted from contact maps [1,2] and forms the scaffolding for all other motifs of RNA structure, the base pairing maps of RNA secondary structure and pseudoknots
From the latter part of the 1950s to the early part of the 1960s, it was quickly recognized from hypochromicity measurements of RNA [3,4,5,6,7,8,9] that there was base pairing [7,8,10,11,12,13], and that these base pairs could result from self-folding of single-stranded RNA—the concept of RNA secondary structure [5]
Summary
In RNA structure, a stem is a segment of double-stranded RNA (dsRNA) forming a duplex that is typically 3 to 10 bps long. Even in the context of more complete modeling of the thermodynamics of various RNA motifs [63], the fundamental underlying model remains the same These base pairing parameters are used in a variety of programs including mfold [64,65,66,67], UNAFold [68], the Vienna package [69,70,71], and a pseudoknot prediction program, vsfold5 [72], and its corresponding suboptimal structure prediction program, vs_subopt [73]. As some RNA structures can exhibit highly variable degrees of stiffness, we are interested in finding out how the length of the duplex might affect the free energy beyond the sequence-dependent 2-nt base pairing parameters, ∆GtAU and ∆Ginit, if at all. We s3imofp1l9y show that a stem model such as the Turner model, it is generally used and often generates good predictions, is not the only possible model that can be shown to fit gtehneeerxatpeesrigmoeondtaplreddaitcat.ioBnosth, issenqoutetnhcee/osntrluycptuorsesidbaletamanoddetlhtehramt ocdaynnbaemsihcodwatnataorefitfitthteed euxspienrgimaen- tgarladdaitean. tB-doethscseenqtu(eGncDe)/sfittrtuinctgurperodgatraamanddetvheelrompoeddyinna-mhoicudseataanadreafinttaepdpursoiancgh au—signrgadaigenent-edteicscaelgnot r(iGthDm) fi(GttAin;gbpasroedgroanmtdheevPeyloepvoedlvienp-haockuasgeeanasd aandraipvperr)otaochbuuislidn2g-ant gpeanreatmic eatlegrosritthhamt a(GreAn; bataisveedtoontthhee cPryoesvs-ollivnekipnagckeangteroapsya d(CriLvEe)r)mtoobdueilld[520-–n5t3p].arFaomr ectoemrstphaatriasroenn, aittiivseatolsothue scerdossto-lifnikt idnugpelnetxreospuys(iCnLgEt)hme oTduerln[e5r0–m5o3d].eFl o(rEcqoumatpioanris(o1n)), iwt iisthaltshoe ussteadndtoarfidtbdeunpclhemxeasrkusdinatgatuhseeTdutrongerenmeoradteelt(hEeqmuaotdioenl p(1a)r)awmiettherths.e standard benchmark data used to generate the model parameters
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