Simulation of Interactions between Nucleic Acid Bases by Refined Atom-Atom Potential Functions

Poltev, V. I.; Shulyupina, N. V.

doi:10.1080/07391102.1986.10508459

Cited by 117 publications

(68 citation statements)

References 74 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The conformations of backbones connecting adjacent bases are calculated with a specialized chain closure algorithm (38), which ensures that bond lengths and bond angles have standard values. The conformational energy is calculated in vacuo with a distance-dependent dielectric constant, using an empirical force field optimized for nucleic acids (22,39). To take the shielding effect of counterions into account, the phosphate groups are assumed to be electroneutral.…”

Section: Methodsmentioning

confidence: 99%

A Triple Helix within a Pseudoknot Is a Conserved and Essential Element of Telomerase RNA

Shefer

Brown

Gorkovoy

et al. 2007

Molecular and Cellular Biology

109

View full text Add to dashboard Cite

Telomerase copies a short template within its integral telomerase RNA onto eukaryotic chromosome ends, compensating for incomplete replication and degradation. Telomerase action extends the proliferative potential of cells, and thus it is implicated in cancer and aging. Nontemplate regions of telomerase RNA are also crucial for telomerase function. However, they are highly divergent in sequence among species, and their roles are largely unclear. Using in silico three-dimensional modeling, constrained by mutational analysis, we propose a three-dimensional model for a pseudoknot in telomerase RNA of the budding yeast Kluyveromyces lactis. Interestingly, this structure includes a U-A ⅐ U major-groove triple helix. We confirmed the triple-helix formation in vitro using oligoribonucleotides and showed that it is essential for telomerase function in vivo. While triplex-disrupting mutations abolished telomerase function, triple compensatory mutations that formed pH-dependent G-C ⅐ C ؉ triples restored the pseudoknot structure in a pH-dependent manner and partly restored telomerase function in vivo. In addition, we identified a novel type of triple helix that is formed by G-C ⅐ U triples, which also partly restored the pseudoknot structure and function. We propose that this unusual structure, so far found only in telomerase RNA, provides an essential and conserved telomerasespecific function.Telomerase, a ribonucleoprotein reverse transcriptase, makes up for losses caused by incomplete DNA replication and degradation, by adding species-specific, 5-to 26-nucleotide (nt) repeats onto the telomere termini (reviewed in reference 2). The telomerase complex contains an RNA subunit (TER) (TLC1 in Saccharomyces cerevisiae), a catalytic reverse transcriptase (TERT) (Est2 in S. cerevisiae), and several other protein components. Unlike other reverse transcriptases, telomerase specializes in repeatedly copying a short RNA template within its integral RNA component.TERs are highly divergent, being conserved in sequence only among closely related species. Phylogenetic covariation was used to predict conserved secondary structures for evolutionarily close species of ciliates (14, 24), vertebrates (4), Kluyveromyces budding yeasts of the K. marxianus cluster (31, 32), and Saccharomyces sensu stricto (3,7,13,37). Limited similarity in the general architecture was observed among these models, consisting of three long arms and a catalytic core domain (4, 13). Although nontemplate regions are essential for the assembly, regulation, and function of telomerase, their specific roles are still unclear (reviewed in reference 30). We hypothesized that important functional elements would exhibit better conservation in their tertiary structures, rather than in their secondary structures or sequences. Solving these tertiary structures may provide insights into their conserved functions.Pseudoknot elements were found to be critical for telomerase function in ciliates (28), vertebrates (4), and Kluyveromyces (32). For S. cerevisiae, alternative pseud...

show abstract

Section: Methodsmentioning

confidence: 99%

A Triple Helix within a Pseudoknot Is a Conserved and Essential Element of Telomerase RNA

Shefer

Brown

Gorkovoy

et al. 2007

Molecular and Cellular Biology

109

View full text Add to dashboard Cite

show abstract

“…2a shows the predicted five imino proton signals. Three of the signals are located in the normal hydrogenbonded imino proton region (12)(13)(14) ppm), and the other two are upfield (10.4 and 10.5 ppm). NOE and temperature results were used for assignments.…”

mentioning

confidence: 99%

“…Early studies have shown that a single G&A mismatch could be readily incorporated into DNA helices and the G-A mismatch was resistant to single-strand nucleases (12,13). In neutral aqueous buffer with the normal base tautomers, there are four types of G&A mismatch base pairs (14), and these can be grouped by imino (Fig. 1, structures A and B) or amino hydrogen bond (Fig.…”

mentioning

confidence: 99%

NMR and molecular modeling evidence for a G.A mismatch base pair in a purine-rich DNA duplex.

Liu

Zon

Wilson

1991

Proc. Natl. Acad. Sci. U.S.A.

151

View full text Add to dashboard Cite

ABSTRACT1H NMR experiments indicate that the oligomer 5'-d(ATGAGCGAATA) forms an unusual 10-base-pair duplex with 4 G-A base pairs (underlined) and a 3' unpaired adenosine. NMR results indicate that guanosine imino protons of the G-A mismatches are not hydrogen bonded but are stacked in the helix. A G -* I substitution in either G-A base pair causes a dramatic decrease in duplex stability and indicates that hydrogen bonding of the guanosine amino group is critical. Nuclear Overhauser effect spectroscopy (NOESY) and two-dimensional correlated spectroscopy (COSY) results indicate that the overall duplex conformation is in the B-family. Cross-strand NOEs in two-dimensional NOESY spectra between a mismatched AH2 and an AHl' ofthe other mismatched base pair and between a mismatched GH8 and GNH1 of the other mismatch establish a purine-purine stacking pattern, adenosine over adenosine and guanosine over guanosine, which strongly stabilizes the duplex. A computer graphics molecular model of the unusual duplex was constructed with G-A base pairs containing A-NH2 to GN3 and G-NH2 to AN7 hydrogen bonds and B-form base pairs on both sides of the G'A pairs [5'-d(ATGAGC)J. The energy-minimized duplex satisfies all experimental constraints from NOESY and COSY results. A hydrogen bond from G-NH2 of the mismatch to a phosphate oxygen is predicted.Mismatches in DNA can arise, for example, in specific structures such as telomeres (1, 2), during replication, and in genetic recombination. If not corrected, the mismatches may lead to point mutations in subsequent replication (3-7). G-A mismatches are of particular interest because they are a common structural element in RNA folding (8)(9)(10)(11). Early studies have shown that a single G&A mismatch could be readily incorporated into DNA helices and the G-A mismatch was resistant to single-strand nucleases (12, 13). In neutral aqueous buffer with the normal base tautomers, there are four types of G&A mismatch base pairs (14), and these can be grouped by imino (Fig. 1, structures A and B) or amino hydrogen bond (Fig. 1, structures C and D) pairs with respect to guanosine. Several structural studies by single-crystal x-ray diffraction and NMR methods have shown that G-A mismatches are conformationally variable. Base pairs of types A and B but not C and D have been observed (7,(15)(16)(17)(18)(19)(20).In studies of the interaction of antisense oligonucleotides with 11-base analogs of ras p21 mRNA (21), we discovered a sequence, termed 2C, 5'-d(ATGAGCGAATA), that formed an unusually stable duplex (22). Eight of 11 bases in sequence 2C are purines and, from base-pairing possibilities, an unusual duplex with four G-A mismatch base pairs was proposed for this sequence (Fig. 2a) (22). We have undertaken NMR studies to define this unusual duplex in more detail and report here the observations of G-A mismatches oftype D and unusual purine purine base stacking in a B-form duplex.MATERIALS AND METHODS Oligonucleotides were synthesized as described (22). NMR experiments were performed on a Varian...

show abstract

“…(Note that the remaining nine of the total of 53 base-pairs mentioned above are variants in which bases are protonated but no additional hydrogen bonds are formed and thus have redundant hydrogen bonding patterns; see Figure 2). Of the 30 unprotonated arrangements, two unexpected G:U pairs were found (#9, #11 in Figure 2) that were not identified in previous modeling studies, 13,14 probably due to the close proximity of the carbonyl groups of U and the C1 0 atom of G, and have not been included in recent base-pair compilations. 39 In both G:U pairs, the pyrimidine base hydrogen bonds to the N3 imino and N2 amino groups of G, similar to a G:C arrangement (#7) that was previously modeled but not included in earlier base-pair compilations.…”

Section: Base-pairsmentioning

confidence: 87%

“…3,11,12 Later modeling studies identified one additional G:C arrangement. 13,14 Most of these predicted pairings have been observed experimentally either in RNA structures or in DNA helices containing mismatched bases. 5 The potential diversity of base-triples is less well understood and relatively few have been observed.…”

Section: Introductionmentioning

confidence: 99%

Structural Diversity and Isomorphism of Hydrogen-bonded Base Interactions in Nucleic Acids

Walberer

Cheng

Frankel

2003

Journal of Molecular Biology

View full text Add to dashboard Cite

The wide structural diversity of RNA results in part from the diversity of non-Watson-Crick interactions between bases. To examine the repertoire of possible hydrogen bond interactions among bases, we computed databases of base-pairs and base-triples by systematically matching all possible hydrogen-bond donors and acceptors between bases and evaluating the geometries of each planar configuration. For base-pairs, we find 53 arrangements having at least two hydrogen bonds, including 23 pairs with protonated bases that have not previously been modeled. A comparison with experimentally observed base-pairs reveals an unexpected G:U pair recently observed in the ribosome. For base-triples, we find 840 arrangements in which the three bases are constrained by a total of at least three hydrogen bonds. Base-triples in particular exhibit a wide range of structural diversity, suggesting how compact or elongated nucleic acid structures may be constructed using different hydrogenbonding patterns. Base-pair and base-triple conformations were systematically compared to identify structurally isomorphic combinations, and the experimentally observed arrangements within double and triple helices are among the most isomorphic. Unexpectedly, however, other combinations in the database are even more isomorphic, including several in which all-purine arrangements overlap with all-pyrimidine arrangements. These studies highlight some of the combinatoric and geometric versatility of base interactions and help provide a framework for analyzing and modeling isomorphic interactions and potentially for designing novel nucleic acid structures.

show abstract

Simulation of Interactions between Nucleic Acid Bases by Refined Atom-Atom Potential Functions

Cited by 117 publications

References 74 publications

A Triple Helix within a Pseudoknot Is a Conserved and Essential Element of Telomerase RNA

A Triple Helix within a Pseudoknot Is a Conserved and Essential Element of Telomerase RNA

NMR and molecular modeling evidence for a G.A mismatch base pair in a purine-rich DNA duplex.

Structural Diversity and Isomorphism of Hydrogen-bonded Base Interactions in Nucleic Acids

Contact Info

Product

Resources

About