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Improved Model for Predicting the Free Energy Contribution of Dinucleotide Bulges to RNA Duplex Stability.

ABSTRACT: Predicting the secondary structure of RNA is an intermediate in predicting RNA three-dimensional structure. Commonly, determining RNA secondary structure from sequence uses free energy minimization and nearest neighbor parameters. Current algorithms utilize a sequence-independent model to predict free energy contributions of dinucleotide bulges. To determine if a sequence-dependent model would be more accurate, short RNA duplexes containing dinucleotide bulges with different sequences and nearest neighbor combinations were optically melted to derive thermodynamic parameters. These data suggested energy contributions of dinucleotide bulges were sequence-dependent, and a sequence-dependent model was derived. This model assigns free energy penalties based on the identity of nucleotides in the bulge (3.06 kcal/mol for two purines, 2.93 kcal/mol for two pyrimidines, 2.71 kcal/mol for 5'-purine-pyrimidine-3', and 2.41 kcal/mol for 5'-pyrimidine-purine-3'). The predictive model also includes a 0.45 kcal/mol penalty for an A-U pair adjacent to the bulge and a -0.28 kcal/mol bonus for a G-U pair adjacent to the bulge. The new sequence-dependent model results in predicted values within, on average, 0.17 kcal/mol of experimental values, a significant improvement over the sequence-independent model. This model and new experimental values can be incorporated into algorithms that predict RNA stability and secondary structure from sequence.

SUBMITTER: Tomcho JC

PROVIDER: S-EPMC5058784 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Improved Model for Predicting the Free Energy Contribution of Dinucleotide Bulges to RNA Duplex Stability.

Tomcho Jeremy C JC Tillman Magdalena R MR Znosko Brent M BM

Biochemistry 20150819 34

Predicting the secondary structure of RNA is an intermediate in predicting RNA three-dimensional structure. Commonly, determining RNA secondary structure from sequence uses free energy minimization and nearest neighbor parameters. Current algorithms utilize a sequence-independent model to predict free energy contributions of dinucleotide bulges. To determine if a sequence-dependent model would be more accurate, short RNA duplexes containing dinucleotide bulges with different sequences and neares ...[more]

PMID: 26286708

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Project description: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.

Project description:Canonical forms of duplex DNA are known to sample well-defined regions of the alpha, beta, gamma, epsilon, and zeta dihedral angles that define the conformation of the phosphodiester linkage in the backbone of oligonucleotides. While extensive studies of base composition and base sequence dependent effects on the sampling of the A, B1, and BII canonical forms of duplex DNA have been presented, our understanding of the intrinsic contribution of the five dihedral degrees of freedom associated with the phosphodiester linkage to the conformational properties of duplex DNA is still limited. To better understand this contribution, ab initio quantum mechanical (QM) calculations were performed on a model compound representative of the phosphodiester backbone to systematically sample the energetics about the alpha, beta, gamma, epsilon, and zeta dihedral angles relevant to the conformational properties of duplex DNA. Low-energy regions of dihedral potential energy surfaces are shown to correlate with the regions of dihedral space sampled in experimental crystal structures of the canonical forms of DNA, validating the utility of the model compound and emphasizing the contribution of the intrinsic mechanical properties of the phosphodiester backbone to the conformational properties of duplex DNA. Those contributions include the relative stability of the A, BI, and BII conformations of duplex DNA, where the gas-phase energetics favor the BI form over the A and BII forms. In addition, subtle features of the potential energy surfaces mimic changes in the probability distributions of alpha, beta, gamma, epsilon, and zeta dihedral angles in A, BI, and BII forms of DNA as well as with conformations sampled in single-stranded DNA. These results show that the intrinsic mechanical properties of the phosphodiester backbone make a significant contribution to conformational properties of duplex DNA observed in the condensed phase and allow for the prediction that single-stranded DNA primarily samples folded conformations thereby possibly lowering the entropic barrier to the formation of duplex DNA.

Project description:BackgroundSequence determines the three-dimensional structure of RNAs, and thereby plays an important role in carrying out various biological functions. RNA duplexes containing Watson-Crick (WC) basepairs, interspersed with non-Watson-Crick basepairs, are the dominant structural unit and form the scaffold for the 3-dimensional structure of RNA. It is therefore crucial to understand the geometric variation in the dinucleotide steps that form the helices. We have carried out a detailed analysis of the dinucleotide steps formed by AU and GC Watson-Crick basepairs in RNA structures (both free and protein bound) and compared the results to that seen in DNA. Further, the effect of protein binding on these steps was examined by comparing steps in free RNA structures with protein bound RNA structures.ResultsCharacteristic sequence dependent geometries are observed for the RR, RY and YR type of dinucleotide steps in RNA. Their geometric parameters show correlated variations that are different from those observed in B-DNA helices. Subtle, but statistically significant differences are seen in roll, slide and average propeller-twist values, between the dinucleotide steps of free RNA and protein bound RNA structures. Many non-canonical cross-strand and intra-strand hydrogen bonds were identified that can stabilise the RNA dinucleotide steps, among which YR steps show presence of many new unreported interactions.ConclusionsOur work provides for the first time a detailed analysis of the conformational preferences exhibited by Watson-Crick basepair containing steps in RNA double helices. Overall, the WC dinucleotide steps show considerable conformational variability. Furthermore, we have identified hydrogen bond interactions in several of the dinucleotide steps that could play a role in determining the preferred geometry, in addition to the intra-basepair hydrogen bonds and stacking interactions. Protein binding affects the conformation of the steps that are in direct contact, as well as allosterically affect the steps that are not in direct physical contact.

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Improved Model for Predicting the Free Energy Contribution of Dinucleotide Bulges to RNA Duplex Stability.

Publications

Improved Model for Predicting the Free Energy Contribution of Dinucleotide Bulges to RNA Duplex Stability.

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