Abstract
BackgroundEstimation of DNA duplex hybridization free energy is widely used for predicting cross-hybridizations in DNA computing and microarray experiments. A number of software programs based on different methods and parametrizations are available for the theoretical estimation of duplex free energies. However, significant differences in free energy values are sometimes observed among estimations obtained with various methods, thus being difficult to decide what value is the accurate one.ResultsWe present in this study a quantitative comparison of the similarities and differences among four published DNA/DNA duplex free energy calculation methods and an extended Nearest-Neighbour Model for perfect matches based on triplet interactions. The comparison was performed on a benchmark data set with 695 pairs of short oligos that we collected and manually curated from 29 publications. Sequence lengths range from 4 to 30 nucleotides and span a large GC-content percentage range. For perfect matches, we propose an extension of the Nearest-Neighbour Model that matches or exceeds the performance of the existing ones, both in terms of correlations and root mean squared errors. The proposed model was trained on experimental data with temperature, sodium and sequence concentration characteristics that span a wide range of values, thus conferring the model a higher power of generalization when used for free energy estimations of DNA duplexes under non-standard experimental conditions.ConclusionsBased on our preliminary results, we conclude that no statistically significant differences exist among free energy approximations obtained with 4 publicly available and widely used programs, when benchmarked against a collection of 695 pairs of short oligos collected and curated by the authors of this work based on 29 publications. The extended Nearest-Neighbour Model based on triplet interactions presented in this work is capable of performing accurate estimations of free energies for perfect match duplexes under both standard and non-standard experimental conditions and may serve as a baseline for further developments in this area of research.
Highlights
Estimation of DNA duplex hybridization free energy is widely used for predicting cross-hybridizations in DNA computing and microarray experiments
We introduce in this work an extended NearestNeighbour Model for perfect matches based on triplet interactions, that can approximate free energies for DNA duplexes under a wide range of temperatures, sodium and sequence concentrations
In this work we showed that no major differences exist among free energy estimations of short DNA duplex hybridization when comparing four publicly available programs that employ various sets of thermodynamic parameters
Summary
Estimation of DNA duplex hybridization free energy is widely used for predicting cross-hybridizations in DNA computing and microarray experiments. A number of software programs based on different methods and parametrizations are available for the theoretical estimation of duplex free energies. The accuracy of DNA duplex stability predictions largely varies with sequence length, base composition and experimental conditions. The Thermodynamic Nearest-Neighbour (TNN) Model [1] is a state-of-theart approach that is used to estimate the stability of a single or a pair of DNA (or RNA) molecules based on pairwise base interactions and structural conformations. The MultiRNAFold package (including the PairFold program for duplexes) predicts the minimum free energy, suboptimal secondary structures and free energy changes of one, two, or several interacting nucleic acid sequences. The PairFold algorithm uses dynamic programming to calculate minimum free energy secondary structures and runs in time cubic in the lengths of the input sequences (Θ(n3)). PairFold uses RNA thermodynamic parameters from the Turner Laboratory [10] and DNA thermodynamic parameters from the Mathews and SantaLucia laboratories [11,12]
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