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They then separated the two strands by density, which turned out to be determined by the amount of bound poly IG. In a cesium-chloride density gradient, the strand with more bound poly IG was denser and heavier than its complement. Because the "dense" strand was cytosine-rich, Szybalski and colleagues called it the "C strand.

Intriguingly, the names of Watson and Crick are not mentioned explicitly. In time, the "W strand" and the "C strand" acquired unabbreviated names, "Watson strand" and "Crick strand," respectively [ 16 ]. Interestingly, in the absence of poly IG , the "dense" C strand had a lower molecular weight than the "light" W strand. Thus, the lexicographic journey of the Watson and Crick strands started with the former denoting the light strand and the latter denoting the heavy strand.

In time, the presence of the poly IG molecule would be forgotten and the definition of the two strands would reverse. Crick became the heavy, purine-rich strand, and Watson became the light, pyrimidine-rich strand [ 17 ].

In the literature, the original definition and its inverse are infrequently used today. When searching for either "Watson strand" or "Crick strand" through Google, the Molecular Biology Glossary at Chang Bioscience is currently the top hit [ 18 ]. This glossary defines the Watson strand as the antisense strand for transcription and the Crick strand as the sense strand. This usage is not only restricted to the online glossary but is also found in the scientific literature [ 19 , 20 ].

Sometimes the Watson and Crick strands are used as arbitrary labels, equivalent to "this strand" and "that strand" [ 22 - 24 ]. Without exception, in all cases in which the two strands are drawn horizontally in a figure, the 5' to 3' sequence on top is called the Watson, and the complementary 3' to 5' sequence at the bottom is designated the Crick [ 14 , 15 , 19 , 22 , 24 - 26 ].

In those rare cases in which the two strands are drawn vertically, the Watson strand is invariably the left-hand strand and Crick is the right-hand one. Arguably the most popular usage today originated with the Saccharomyces Genome Database SGD , which defines the Watson strand as the strand which has its 5'-end at the left telomere and the Crick strand as its complement [ 25 ].

The left telomere is defined based on the pre-genomics linkage maps. Note: the left arms were placed above the centromere if the linkage maps were drawn vertically. The assignment of Watson to the top strand is not arbitrary but rather a reflection of the horizontal drawing convention. This yeast-genome terminology has been partially picked up by other genomicists, e.

Standardized definitions for Watson and Crick strands. Sensu stricto , a genomic reference is used, like a submetacentric centromere gray bar , to define two unequal arms of a chromosome. The Watson strand is the strand of a chromosome that has its 5'-end at the short-arm telomere and its 3'-end at the long-arm telomere. The Crick strand is the strand of that has its 5'-end at the long-arm telomere and its 3'-end at the short-arm telomere. If a chromosome is oriented differently, the designations still apply, providing much needed terminological consistency.

Usage of the terms "Watson strand" and "Crick strands" are discouraged outside of a genomic context. If no genomic reference is possible, then it is acceptable to use these terms sensu lato , where the Watson strand is simply a database's reference strand, and the Crick strand its complement. The Saccharomyces Genome Database utilizes the Watson-strand and Crick-strand designations to assign every gene a systematic name based on its position in the S.

These names begin with a letter denoting the organism, in this case "Y" for yeast, followed by the letters "A" to "P" for chromosomes I to XVI. Next "L" is used to denote the short left arm, and "R" the long right arm. A three-digit number denotes the ordinal position as counted from the centromere. Finally, "W" and "C" indicate whether the gene is located on the Watson or Crick strands, respectively. Thus, the systematic name for ADH1, YOLC, means that the gene is found on chromosome XV, that it is the 86th gene from the centromere on the short arm, and that it is encoded on the Crick strand.

Similarly, YGRW means that enolase I is on chromosome VII, that it is the th gene from the centromere on the long arm, and that it is encoded on the Watson strand. We believe that the existence of competing and contradictory usages of Watson and Crick strands leads to confusion, especially as scientific publications become more and more integrated with automated databases.

For instance, a DNA sequence may concurrently be a Crick sense strand, a Watson light strand, a Crick leading strand, and may be located on the Watson genomic strand. This confusion of terminology will cause problems for automated literature mining. Biological research has become so vast that the ability of individuals to keep up with the literature relevant to their research has reached a breaking point [ 28 , 29 ].

In order to cope with the information explosion, scientists are starting to utilize software that automates the discovery of relevant peer-reviewed literature. The development of such software is an active area of research in bioinformatics and computational linguistics [ 28 , 29 ].

Such techniques are predicated upon the existence of unambiguous scientific terminology. Can we standardize the terms "Watson strand" and "Crick strand"? In biology, the principle of precedence or "original intent" is sometimes used to decide among competing terminologies. This is certainly the case in taxonomy, in which, with few exceptions, the valid name for a species is the first name that was published, and the rest are invalid "junior synonyms.

In the case of the strand terminology, this principle would dictate the use of the least common and least useful sense in the literature. We propose instead to use the terms "Watson strand" and "Crick strand" in the sense developed by yeast genomicists and used by other eukaryotic genome projects. Not only is this usage consistent and useful, but gene names and genomic locations often rely on them.

Given the amount of effort already spent on standardizing such databases, and their influence on other disciplines, we feel that the genomic definition of Watson and Crick strands has the most mass behind it. Specifically, we find that the unambiguous usage of the Saccharomyces Genome Database to be the most useful. The chromosome is oriented so that shorter arm is on the left and the longer arm on the right.

Furthermore, the top strand has its 5'-end at the left short-arm telomere and its 3'-end at the right long-arm telomere. This strand is the Watson strand. Similarly, the bottom strand has its 5'-end at the right telomere and its 3' at the left telomere and is the Crick strand. We further propose that "top", "forward", and "plus" be used as synonyms for the Watson strand and "bottom", "reverse", and "minus" for the Crick strand. We note, however, that this suggestion does not provide a universal solution to all double-stranded DNAs; it deprives prokaryotes, centromere-less chromosomes, chromosomes with multiple centromeres, as well as double-stranded DNA viruses of their Watson and Crick strands, and does not even touch upon the problem of triple-stranded DNA, with its Watson, Crick and Hoogsteen strands [ 31 ].

In many of these situations, a genomic feature other than a centromere can be used to orient chromosomes unambiguously. For circular chromosomes, the origin of replication may be used in place of the centromere, while the location of termination can define a cutting point to create short and long arms. If it is ultimately impossible to distinguish Watson and Crick strands using biological properties, then we propose that Watson should refer to the stand arbitrarily used as a reference in a database i.

With this two level approach, our proposal offers a nearly universal solution for unambiguously using Watson and Crick stand terminology, which should improve clarity and annotation. John M. Logsdon, Jr. This is an interesting paper that makes a single important suggestion that I readily endorse. The historical backdrop that the authors develop as grist for the recommendation is in itself a worthwhile and enjoyable read. I am not an expert in scientific terminology.

Thus I will discuss my personal experience and cannot guarantee that my opinion is correct. However, this term cannot be used for a fragment of DNA which contains this mutable motif because this is a biological sequence object. However, I do not think that it is a good idea to assign names of people to DNA strands as these strands are biological objects.

Sometimes DNA is single-stranded, and in this case the logic proposed by the authors cannot be applied. In the case of the yeast genome, I would prefer to use terms "direct" or "complementary" strand and, accordingly, "D" and "C" instead of "W" and "C" in the name of genes because it will be easier to immediately interpret these names. Of course, one needs to keep in mind that some traditional names of biological entities are inseparably linked to the names of their discoverers e.

Authors' Comments : We regard eponyms--terms based on or derived from a person's name--much more positively than Dr. Rogozin, whether they are applied to concepts or material entities. In fact, as we are from the University of Houston an eponym in the United States of America another eponym , we would like to encourage the use of eponyms as a celebration of scientists and their work.

Nomenclature in science should be exact, unambiguous, and if possible, pronounceable; no additional caution is necessary for eponymous nomenclature. This is an interesting, worthwhile, and scholarly paper. I think it should be published, but I have a request. Can the authors suggest a convention for circular chromosomes and plasmids based on origins of replication oris?

Authors' Comments : In revision, we propose that the origin of replication and the location of termination can be used instead of the centromere and the telomeres, respectively. However, this might not be sufficient if the location of termination is evenly spaced from the origin of replication. In addition, there appears to be much variation in the nature of origination and termination of replication on circular chromosomes, and our proposal is probably not nuanced enough to handle every case.

But I bet we can find yeast linkage maps where the chromosomes are drawn as vertical lines short hen top? It might be interesting to find out when and why that convention was chosen, or to point out that the authors could not find out whence it came maybe a learned reader will enlighten us. How did Morgan draw chromosomes? Does someone from the yeast genomics community know how the W-C convention started B Dujon? And then compare the reads in those to my original FASTQs, I find that they are indeed reverse complemented, for instance:.

This came up because recently I was iterating through BAMs using pysam , trying to re-align unmapped reads, and for my particular purpose I wanted to have both of their sequences in the same orientation, i. This was confusing at first because zero, one or both of them might already be reverse-complemented in the SEQ field.

The most conceptually straightforward way is just to reverse complement whichever neither, one or both have. Addendum : for BWA, at least, the proper pair flag depends not only on the FR orientation but also on insert size being within a certain range from BWA manual :. For mapping Illumina short-insert reads to the human genome, x is about sigma away from the mean.

Quartiles, mean, variance and x will be printed to the standard error output. Eric Vallabh Minikel is on a lifelong quest to prevent prion disease.

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In any sequencing technology, you PCR amplify the individual DNA fragments once they have hybridized to flowcells or beads. This means you end up with both strands of DNA. When you align them to the genome, one read should align to the forward strand, and the other should align to the reverse strand, at a higher base pair position than the first one so that they are pointed towards one another.

This is all for conventional paired-end sequencing. This is different from FR because it means the reverse read aligned at a lower base pair position than the forward read, and thus that they are pointing away from another. When I go back and pull out a sampling of the reads with flag value And then compare the reads in those to my original FASTQs, I find that they are indeed reverse complemented, for instance:.

This came up because recently I was iterating through BAMs using pysam , trying to re-align unmapped reads, and for my particular purpose I wanted to have both of their sequences in the same orientation, i. These contradictory results might be explained by a dynamic interaction at the ends of the third-strand binding region which shift the overall structure from one form to another. If true, this mechanism might have serious implications for the binding of many consecutive third-strands at closely arranged targets.

Enthalpic costs are important when a third-strand approaches the duplex for binding. The resulting fifty percent increase in the concentration of negative charges due to the insertion of a third phosphate backbone makes binding of a third-strand to a duplex weaker than that between the two strands of a duplex. Thus, melting temperatures seen for dissociation of third-strands are, depending upon third-strand length, substantially less than those observed for their target duplexes.

Digression from the third-strand binding code Fosella et al and variations in solvent conditions can also affect the observed T m value for third-strand binding. Short oligonucleotides of less than fifteen residues usually do not bind stably and generate only minor interactions with their target. As mentioned, third-strand binding strength can be changed by modifying certain solvent conditions.

Higher cationic concentrations, for example, produce more effective charge shielding, alleviating the electrostatic repulsion due to the close proximity of the three phosphate backbones. Temperature can also be lowered to help stabilize triplexes.

Polyamines and other positively charged ions help stabilize a triplex structure. Spermine, spermidine and benzo[e]pyridoindole help stabilize both inter- and intramolecular triplexes Sridhara-Rao Hydrogen bonding between bases, van der Waal interactions, and base stacking contribute to the overall energy of binding. The bases of the third-strand can also be modified to improve triplex stability.

However, when C is methylated at C5, the pK a of the resulting 5-methyl-2'-deoxycytosine m 5 C is significantly higher, which enhances the binding strength to the corresponding G of the target. Therefore, lower pH is often favored in binding third-strands containing non-modified C.

Povsic and Dervan have shown that m 5 C increases third-strand binding affinity This effect could be due to the creation of a hydrophobic region around the triplex that generates favorable entropic effects Xodo et al It is postulated that the planar prosthetic group increases base stacking interactions and, in a manner similar to m 5 C, increases the entropic energy of the overall structure Froehler et al

INVESTISSEMENTS INTERNATIONAUX ET ARBITRAGE BETTING

Recently, we have been able to examine mismatching of guanine-thymine base pairs in left-handed Z-DNA at atomic resolution 1A. A minimum amount of distortion of the sugar phosphate backbone is found in the G x T pairing in which the bases are held together by two hydrogen bonds in the wobble pairing interaction. Because of the high resolution of the analysis we can visualize water molecules which fill in to accommodate the other hydrogen bonding positions in the bases which are not used in the base-base interactions.

Studies on other DNA oligomers have revealed that other types of non-Watson-Crick hydrogen bonding interactions can occur. Hoogsteen base pairs make a modified helix which is distinct from the Watson-Crick double helix. Studies show that both loop nucleotides and loop closing pairs affect binding affinity. The effect of S-substitution on the O6 guanine site of a mer DNA duplex containing a G:T mismatch is studied using molecular dynamics.

The structure, dynamic evolution and hydration of the S-substituted duplex are compared with those of a normal duplex, a duplex with S-substitution on guanine, but no mismatch and a duplex with just a G:T mismatch. The S-substituted mismatch leads to cell death rather than repair.

This leads to a cycle of futile repair ending in DNA breakage and cell death. We find that some structural features of the helix are similar for the duplex with the G:T mismatch and that with the S-substituted mismatch , but differ from the normal duplex, notably the helical twist. These differences arise from the change in the hydrogen-bonding pattern of the base pair. However a marked feature of the S-substituted G:T mismatch duplex is a very large opening. This showed considerable variability.

It is suggested that this enlarged opening would lend support to an alternative model of cell death in which the mismatch protein attaches to thioguanine and activates downstream damage-response pathways.

Attack on the sulphur by reactive oxygen species, also leading to cell death, would also be aided by the large, variable opening. Hoogsteen base-pairing involves a degree rotation of the purine base relative to Watson-Crick base-pairing within DNA duplexes, creating alternative DNA conformations that can play roles in recognition , damage induction, and replication. We observe sequence-specific variations in Hoogsteen base-pair energetic stabilities that are comparable to variations in Watson-Crick base-pair stability, with Hoogsteen base-pairs being more abundant for energetically less favorable Watson-Crick base-pairs.

Our results suggest that the variations in Hoogsteen stabilities and rates of formation are dominated by variations in Watson-Crick base pair stability, suggesting a late transition state for the Watson-Crick to Hoogsteen conformational switch.

The occurrence of sequence and position-dependent Hoogsteen base-pairs provide a new potential mechanism for achieving sequence-dependent DNA transactions. These changes in Msh2-Msh3 function depend on the presence of A.

A mispaired bases in the stem of the hairpin and on the hairpin DNA structure per se. The structural impact of DNA mismatches. Rossetti, Giulia; Dans, Pablo D. The structure and dynamics of all the transversion and transition mismatches in three different DNA environments have been characterized by molecular dynamics simulations and NMR spectroscopy. We found that the presence of mismatches produced significant local structural alterations, especially in the case of purine transversions.

Mismatched pairs often show promiscuous hydrogen bonding patterns, which interchange among each other in the nanosecond time scale. This therefore defines flexible base pairs , where breathing is frequent, and where distortions in helical parameters are strong, resulting in significant alterations in groove dimension. Even if the DNA structure is plastic enough to absorb the structural impact of the mismatch , local structural changes can be propagated far from the mismatch site, following the expected through-backbone and a previously unknown through-space mechanism.

The structural changes related to the presence of mismatches help to understand the different susceptibility of mismatches to the action of repairing proteins. The uracil DNA glycosylase superfamily consists of several distinct families.

Here, we report the identification of an important structural determinant that underlies the functional difference between MUG and UNG. Binding and kinetic analysis demonstrate that the MUG-K68N substitution results in enhanced ground state binding and transition state interactions. The implications of this study in the origin of life are discussed.

The protein toxin alpha-hemolysin form nanometer scale channels across lipid membranes. Our lab uses a single channel in an artificial lipid bilayer in a patch clamp device to capture and examine individual DNA molecules. This nanopore detector used with a support vector machine SVM can analyze DNA hairpin molecules on the millisecond time scale. We distinguish duplex stem length, base pair mismatches , loop length, and single base pair differences. The residual current fluxes also reveal structural molecular dynamics elements.

DNA end-fraying terminal base pair dissociation can be observed as near full blockades, or spikes, in current. Method for sequencing DNA base pairs. The DNA structure is scanned by the STM probe tip, and, as it is being scanned, the DNA structure is separately subjected to a sequence of infrared radiation from four different sources, each source being selected to preferentially excite one of the four different bases in the DNA structure.

Each particular base being scanned is subjected to such sequence of infrared radiation from the four different sources as that particular base is being scanned. The DNA structure as a whole is separately imaged for each subjection thereof to radiation from one only of each source. Mechanism for verification of mismatched and homoduplex DNAs by nucleotides-bound MutS analyzed by molecular dynamics simulations.

As for MutS, the disordered loops in the ATPase domains, which are considered to be necessary for the induction of DNA repair, were close to away from the nucleotide-binding sites in the ATPase domains when the nucleotides were not bound to MutS.

Conformational analysis by principal component analysis showed that the nucleotide binding changed modes which have structurally solid ATPase domains and the large bending motion of the DNA from higher to lower frequencies. In the MutS- mismatched DNA complex bound to two nucleotides, the bending motion of the DNA at low frequency modes may play a role in triggering the formation of the sliding clamp for the following DNA-repair reaction step.

Proteins ; Nucleic acid duplexes incorporating a dissociable covalent base pair. We have used molecular modeling techniques to design a dissociable covalently bonded base pair that can replace a Watson-Crick base pair in a nucleic acid with minimal distortion of the structure of the double helix. We introduced this base pair into a potential precursor of a nucleic acid double helix by chemical synthesis and have demonstrated efficient nonenzymatic template-directed ligation of the free hydroxyl groups of the base pair with appropriate short oligonucleotides.

The nonenzymatic ligation reactions, which are characteristic of base paired nucleic acid structures, are abolished when the covalent base pair is reduced and becomes noncoplanar. This suggests that the covalent base pair linking the two strands in the duplex is compatible with a minimally distorted nucleic acid double-helical structure. Differential stabilities and sequence-dependent base pair opening dynamics of Watson-Crick base pairs with 5-hydroxymethylcytosine, 5-formylcytosine, or 5-carboxylcytosine.

Three modified Dickerson-Drew dodecamer DDD sequences, amenable to crystallographic and spectroscopic analyses and containing the 5'-CG-3' sequence associated with genomic cytosine methylation, containing 5hmC, 5fC, or 5caC placed site-specifically into the 5'-T 8 X 9 G 10 -3' sequence of the DDD, were compared.

Both 5hmC and 5fC increased imino proton exchange rates and calculated rate constants for base pair opening at the neighboring base pair A 5 :T 8 , whereas 5caC did not. At the oxidized base pair G 4 :X 9 , 5fC exhibited an increase in the imino proton exchange rate and the calculated kop.

In all cases, minimal effects to imino proton exchange rates occurred at the neighboring base pair C 3 :G No evidence was observed for imino tautomerization, accompanied by wobble base pairing , for 5hmC, 5fC, or 5caC when positioned at base pair G 4 :X 9 ; each favored Watson-Crick base pairing.

However, both 5fC and 5caC exhibited intranucleobase hydrogen bonding between their formyl or carboxyl oxygens, respectively, and the adjacent cytosine N 4 exocyclic amines. However, they do not correlate with differential excision of 5hmC, 5fC, or 5caC by TDG, which may be mediated by differences in transition states of the enzyme-bound complexes.

Both 5hmC and 5fC increased imino proton exchange rates and calculated rate constants for base pair opening at the neighboring base pair A5:T8, whereas 5caC did not. At the oxidized base pair G4:X9, 5fC exhibited an increase in the imino proton exchange rate and the calculated kop. In all cases, minimal effects to imino proton exchange rates occurred at the neighboring base pair C3:G No evidence was observed for imino tautomerization, accompanied by wobble base pairing , for 5hmC, 5fC, or 5caC when positioned at base pair G4:X9; each favored Watson—Crick base pairing.

However, both 5fC and 5caC exhibited intranucleobase hydrogen bonding between their formyl or carboxyl oxygens, respectively, and the adjacent cytosine N4 exocyclic amines. Differential stabilities and sequence-dependent base pair opening dynamics of Watson—Crick base pairs with 5-hydroxymethylcytosine, 5-formylcytosine, or 5-carboxylcytosine. Three modified Dickerson—Drew dodecamer DDD sequences, amenable to crystallographic and spectroscopic analyses and containing the 5'-CG-3' sequence associated with genomic cytosine methylation, containing 5hmC, 5fC, or 5caC placed site-specifically into the 5'-T 8X 9G ' sequence of the DDD, were compared.

Both 5hmC and 5fC increased imino proton exchange rates and calculated rate constants for base pair opening at the neighboring base pair A 5:T 8, whereas 5caC did not. At the oxidized base pair G 4:X 9, 5fC exhibited an increase in the imino proton exchange rate and the calculated k op. In all cases, minimal effects to imino proton exchange rates occurred at the neighboring base pair C 3:G No evidence was observed for imino tautomerization, accompanied by wobble base pairing , for 5hmC, 5fC, or 5caC when positioned at base pair G 4:X 9; each favored Watson—Crick base pairing.

Furthermore, they do not correlate with differential excision of 5hmC, 5fC, or 5caC by TDG, which may be mediated by differences in transition states of the enzyme-bound complexes. Base pair probability estimates improve the prediction accuracy of RNA non-canonical base pairs. Prediction of RNA tertiary structure from sequence is an important problem, but generating accurate structure models for even short sequences remains difficult. Predictions of RNA tertiary structure tend to be least accurate in loop regions, where non-canonical pairs are important for determining the details of structure.

Non-canonical pairs can be predicted using a knowledge-based model of structure that scores nucleotide cyclic motifs, or NCMs. In this work, a partition function algorithm is introduced that allows the estimation of base pairing probabilities for both canonical and non-canonical interactions.

Pairs that are predicted to be probable are more likely to be found in the true structure than pairs of lower probability. Pair probability estimates can be further improved by predicting the structure conserved across multiple homologous sequences using the TurboFold algorithm. These pairing probabilities, used in concert with prior knowledge of the canonical secondary structure, allow accurate inference of non-canonical pairs, an important step towards accurate prediction of the full tertiary structure.

Software to predict non-canonical base pairs and pairing probabilities is now provided as part of the RNAstructure software package. KlenTaq polymerase replicates unnatural base pairs by inducing a Watson-Crick geometry.

Many candidate unnatural DNA base pairs have been developed, but some of the best-replicated pairs adopt intercalated structures in free DNA that are difficult to reconcile with known mechanisms of polymerase recognition. Here we present crystal structures of KlenTaq DNA polymerase at different stages of replication for one such pair, dNaM-d5SICS, and show that efficient replication results from the polymerase itself, inducing the required natural-like structure.

With the aid of Density Functional Theory DFT , we designed 1,8-naphthyridine-2,7-diamine as a recognition molecule to read DNA base pairs for genomic sequencing by electron tunneling. Our results suggest that the naphthyridine molecule should be able to function as a universal base pair reader in a tunneling gap, generating distinguishable signatures under electrical bias for each of DNA base pairs. With the aid of Density Functional Theory DFT , we designed 1,8-naphthyridine-2,7-diamine as a recognition molecule to read the DNA base pairs for genomic sequencing by electron tunneling.

Closing loop base pairs in RNA loop-loop complexes: structural behavior, interaction energy and solvation analysis through molecular dynamics simulations. The simulations reveal that the mismatch GA base, mediated by a water molecule, leads to a complex that presents the best compromise between flexibility and energetic contributions.

The mismatch CU base pair , in spite of the presence of an inserted water molecule, is too short to achieve a tight interaction at the closing-loop junction and seems to force TAR to reorganize upon binding. An energetic analysis has allowed us to quantify the strength of the interactions of the closing and the loop-loop pairs throughout the simulations.

Although the water-mediated GA closing base pair presents an interaction energy similar to that found on fully geometry-optimized structure, the water-mediated CU closing base pair energy interaction reaches less than half the optimal value.

Unnatural substrates reveal the importance of 8-oxoguanine for in vivo mismatch repair by MutY. To determine the importance of specific steps in the base pair recognition and base removal process of MutY, we have evaluated the effects of modifications of the OG:A substrate on the kinetics of base removal, mismatch affinity and repair to G:C in an Escherchia coli-based assay. Surprisingly, adenine modification was tolerated in the cellular assay, while modification of OG results in minimal cellular repair.

High affinity for the mismatch and efficient base removal require the presence of OG. Taken together, these results suggest that the presence of OG is a critical feature for MutY to locate OG:A mismatches and select the appropriate adenines for excision to initiate repair in vivo prior to replication. We report on the dynamics of base-pair opening in the ATP-binding asymmetric internal loop and flanking base-pairs of the AMP-RNA aptamer complex by monitoring the exchange characteristics of the extremely well resolved imino protons in the NMR spectrum of the complex.

The kinetics of imino proton exchange as a function of basic pH or added ammonia catalyst are used to measure the apparent base-pair dissociation constants and lifetimes of Watson-Crick and mismatched base-pairs , as well as the solvent accessibility of the unpaired imino protons in the complex.

The exchange characteristics of the imino protons identify the existence of four additional hydrogen bonds stabilizing the conformation of the asymmetric ATP-binding internal loop that were not detected by NOEs and coupling constants alone, but are readily accommodated in the previously reported solution structure of the AMP-RNA aptamer complex published from our laboratory.

The hydrogen exchange kinetics of the non-Watson-Crick pairs in the asymmetric internal loop of the AMP-RNA aptamer complex have been characterized and yield apparent dissociation constants alphaKd that range from 10 -2 to 10 Comparative studies of hydrogen exchange of the imino protons in the free RNA aptamer and the AMP-RNA aptamer complex establish that complexation stabilizes not only the bases within the ATP-binding asymmetric internal loop, but also the flanking stem base-pairs two pairs on either side of the binding site.

We also outline some preliminary results related to the exchange properties of a sugar 2'-hydroxyl proton of a guanosine residue involved in a novel hydrogen bond that has been shown to contribute to the immobilization of the bound AMP by the RNA aptamer, and whose resonance is narrow and downfield shifted in the spectrum.

AT base pair anions versus 9-methyl-A 1-methyl-T base pair anions. The anionic base pairs of adenine and thymine, AT - , and 9-methyladenine and 1-methylthymine, MAMT - , have been investigated both theoretically and experimentally in a complementary, synergistic study. This circumstance was mimicked by methylating the sites on both A and T where these sugars would have been tied, viz. The configuration of MAMT - and its lack of electron-induced proton transfer are inter-related.

While evidence is emerging that the Hoogsteen conformation could be a thermodynamically accessible conformation of the DNA duplex and provide a means to expand its functionality, relatively little is known about the molecular mechanism underlying the Watson-Crick WC to HG transition.

In this Perspective, we describe pathways and kinetics for this transition at an atomic level of detail, using the energy landscape perspective. We show that competition between the duplex conformations results in a double funnel landscape, which explains some recent experimental observations. The interconversion pathways feature a number of intermediates, with a variable number of WC and HG base pairs.

The relatively slow kinetics, with possible deviations from two-state behavior, suggest that this conformational switch is likely to be a challenging target for both simulation and experiment. In this work, we have used a Poisson—Boltzmann approach to gain a more detailed and accurate characterization of the electrostatic profile. Roles of the amino group of purine bases in the thermodynamic stability of DNA base pairing.

The energetic aspects of hydrogen-bonded base-pair interactions are important for the design of functional nucleotide analogs and for practical applications of oligonucleotides. The present study investigated the contribution of the 2-amino group of DNA purine bases to the thermodynamic stability of oligonucleotide duplexes under different salt and solvent conditions, using 2'-deoxyriboinosine I and 2'-deoxyribo-2,6-diaminopurine D as non-canonical nucleotides.

The apparent stabilization energy due to the presence of the 2-amino group of G and D varied depending on the salt concentration, and decreased in the water-ethanol mixed solvent. The effects of salt concentration on the thermodynamics of DNA duplexes were found to be partially sequence-dependent, and the 2-amino group of the purine bases might have an influence on the binding of ions to DNA through the formation of a stable base-paired structure.

Our results also showed that physiological salt conditions were energetically favorable for complementary base recognition , and conversely, low salt concentration media and ethanol-containing solvents were effective for low stringency oligonucleotide hybridization, in the context of conditions employed in this study.

Unaccusative Mismatches in Japanese. Two instances of unaccusative verb mismatches in Japanese are examined. An unaccusative mismatch is the situation in which a different accusative diagnostic singles out different classes of intransitive verbs within and across languages. One type of unaccusative mismatch has to do with group C verbs, or verbs of manner with protagonist control.

We report the structure of clusters of 2,4-diaminopyrimidine with 3,7-dimethylxanthine theobromine in the gas phase determined by IR-UV double resonance spectroscopy in both the near-IR and mid-IR regions in combination with ab initio computations. These clusters represent potential alternate nucleobase pairs, geometrically equivalent to guanine-cytosine. We have found the four lowest energy structures, which include the Watson-Crick base pairing motif.

Replication infidelity via a mismatch with Watson—Crick geometry. However, despite substantial progress in understanding the structural basis of error prevention during polymerization, no DNA polymerase has yet been shown to form a natural base—base mismatch with Watson—Crick-like geometry.

All atoms needed for catalysis are present at the active site and in positions that overlay with those for a correct base pair. The mismatch has Watson—Crick geometry consistent with a tautomeric or ionized base pair , with the pH dependence of misinsertion consistent with the latter.

The results support the original idea that a base substitution can originate from a mismatch having Watson—Crick geometry, and they suggest a common catalytic mechanism for inserting a correct and an incorrect nucleotide. Replication infidelity via a mismatch with Watson-Crick geometry. In describing the DNA double helix, Watson and Crick suggested that "spontaneous mutation may be due to a base occasionally occurring in one of its less likely tautomeric forms.

However, despite substantial progress in understanding the structural basis of error prevention during polymerization, no DNA polymerase has yet been shown to form a natural base-base mismatch with Watson-Crick-like geometry. The mismatch has Watson-Crick geometry consistent with a tautomeric or ionized base pair , with the pH dependence of misinsertion consistent with the latter. The results support the original idea that a base substitution can originate from a mismatch having Watson-Crick geometry, and they suggest a common catalytic mechanism for inserting a correct and an incorrect nucleotide.

Hydration of Watson-Crick base pairs and dehydration of Hoogsteen base pairs inducing structural polymorphism under molecular crowding conditions. It has been revealed recently that molecular crowding, which is one of the largest differences between in vivo and in vitro conditions, is a critical factor determining the structure, stability, and function of nucleic acids.

However, the effects of molecular crowding on Watson-Crick and Hoogsteen base pairs remain unclear. In order to investigate directly and quantitatively the molecular crowding effects on base pair types in nucleic acids, we designed intramolecular parallel- and antiparallel-stranded DNA duplexes consisting of Hoogsteen and Watson-Crick base pairs , respectively, as well as an intramolecular parallel-stranded triplex containing both types of base pairs.

However, corresponding values for Watson-Crick formation in the duplex and triplex increased from Furthermore, it was revealed that the opposing effects of molecular crowding on the Hoogsteen and Watson-Crick base pairs were due to different behaviors of water molecules binding to the DNA strands. Understanding the kinetic mechanism of RNA single base pair formation. RNA functions are intrinsically tied to folding kinetics.

The most elementary step in RNA folding is the closing and opening of a base pair. Understanding this elementary rate process is the basis for RNA folding kinetics studies. Previous studies mostly focused on the unfolding of base pairs. The study, which integrates molecular dynamics simulation, kinetic Monte Carlo simulation, and master equation methods, uncovers two alternative dominant pathways: Starting from the unfolded state, the nucleotide backbone first folds to the native conformation, followed by subsequent adjustment of the base conformation.

During the base conformational rearrangement, the backbone either retains the native conformation or switches to nonnative conformations in order to lower the kinetic barrier for base rearrangement. The method enables quantification of kinetic partitioning among the different pathways. Configurations of base-pair complexes in solutions. A theoretical search for the most stable conformations i. The calculations of free energies indicate a significant role of the solvent in determining the conformations of the base-pair complexes.

The application of the continuum method yields preferred conformations in good agreement with experiment. Results of the calculations with this method emphasize the importance of both the electrostatic interactions between the two bases in a complex, and the dipolar interaction of the complex with the entire medium.

In calculations with the solvation shell method, the last term, i. With this modification the prediction of the solvation shell model agrees both with the continuum model and with experiment, i. Crenshaw, Charisse M. Despite the apparent similarity of 8-oxoguanine-cytosine base pairs to normal guanine-cytosine base pairs , cellular base excision repair systems effectively recognize the lesion base.

Here we apply several techniques to examine a single 8-oxoguanine lesion at the center of a nonpalindromic mer duplex oligonucleotide in an effort to determine what, if anything, distinguishes an 8-oxoguanine-cytosine base pair from a normal base pair. The lesion duplex is globally almost indistinguishable from the unmodified parent duplex using CD spectroscopy and UV melting thermodynamics. NMR spectra are also consistent with a well-conserved B-form duplex structure. In the 2D NOESY spectra, base-sugar and imino-imino crosspeaks are strikingly similar between parent and lesion duplexes.

Changes in chemical shift due to the 8oxoG lesion are localized to its complementary cytosine and to the 2—3 base pairs immediately flanking the lesion on the lesion strand. Residues further removed from the lesion are shown to be unperturbed by its presence. This collection of experiments shows that the 8-oxoguanine-cytosine base pair is incredibly stable and similar to the native pair.

Mismatch cleavage by single-strand specific nucleases. We have investigated the ability of single-strand specific sss nucleases from different sources to cleave single base pair mismatches in heteroduplex DNA templates used for mutation and single-nucleotide polymorphism analysis. We found that purified nucleases derived from celery CEL I , mung bean sprouts and Aspergillus S1 were able to specifically cleave nearly all single base pair mismatches tested.

Optimal nicking of heteroduplexes for mismatch detection was achieved using higher pH, temperature and divalent cation conditions than are routinely used for digestion of single-stranded DNA. Surprisingly, crude plant extracts performed as well as the highly purified preparations for this application. These observations suggest that diverse members of the S1 family of sss nucleases act similarly in cleaving non-specifically at bulges in heteroduplexes, and single-base mismatches are the least accessible because they present the smallest single-stranded region for enzyme binding.

We conclude that a variety of sss nucleases and extracts can be effectively used for high-throughput mutation and polymorphism discovery. We recently proposed that TF1, which binds with high affinity Kd was approximately 3 nM to preferred sites within the hydroxymethyluracil hmU -containing phage genome, identifies its binding sites based on sequence-dependent DNA flexibility.

Here, we show that two hmU-A base pair steps coinciding with two previously proposed sites of DNA distortion are critical for complex formation. The affinity of TF1 is reduced fold when both of these hmU-A base pair steps are replaced with A-hmU, G-C, or C-G steps; only modest changes in affinity result when substitutions are made at other base pairs of the TF1 binding site.

Replacement of all hmU residues with thymine decreases the affinity of TF1 greatly; remarkably, the high affinity is restored when the two hmU-A base pair steps corresponding to previously suggested sites of distortion are reintroduced into otherwise T-containing DNA. We suggest that twin hmU-A base pair steps located at the proposed sites of distortion are key to target site selection by TF1 and that recognition is based largely, if not entirely, on sequence-dependent DNA flexibility.

Kinetic selection vs. Earlier analyses suggested that pol active-site steric constraints can amplify DNA free energy differences at the transition state kinetic selection. A recent paper [Olson et al. Here we perform experiments to measure and account for pyrophosphorolysis explicitly. We show that forward and reverse reactions attain steady states far from equilibrium for wrong incorporations such as G opposite T.

Therefore,[Formula: see text]values obtained from such steady-state evaluations ofKeqare not dependent on DNA properties alone, but depend largely on constraints imposed on right and wrong substrates in the polymerase active site. Educational Mismatch and Retirement. Using a panel data set of scientists in the US, we examine the hypothesis that workers in jobs poorly matched to their education are more likely to retire. In pooled estimates, we confirm that the mismatched are more likely to retire and that among retirees, the mismatched retire at younger ages.

Hazard function estimates also support the…. Deficiencies in mismatch repair MMR are associated with carcinogenesis. Rhodium metalloinsertors bind to DNA base mismatches with high specificity and inhibit cellular proliferation preferentially in MMR-deficient cells versus MMR-proficient cells. A family of chrysenequinone diimine complexes of rhodium with varying ancillary ligands that serve as DNA metalloinsertors has been synthesized, and both DNA mismatch binding affinities and antiproliferative activities against the human colorectal carcinoma cell lines HCTN and HCTO, an isogenic model system for MMR deficiency, have been determined.

Significantly, binding affinities are found to be inversely related to ancillary ligand size and directly related to differential inhibition of the HCT cell lines. The observed trend in binding affinity is consistent with the metalloinsertion mode where the complex binds from the minor groove with ejection of mismatched base pairs.

The correlation between binding affinity and targeting of the MMR-deficient cell line suggests that rhodium metalloinsertors exert their selective biological effects on MMR-deficient cells through mismatch binding in vivo. Physics of base-pairing dynamics in DNA. As a key molecule of life, Deoxyribo-Nucleic Acid DNA is the focus of numbers of investigations with the help of biological, chemical and physical techniques.

From a physical point of view, both experimental and theoretical works have brought quantitative insights into DNA base-pairing dynamics that we review in this Report, putting emphasis on theoretical developments. We discuss the dynamics at the base-pair scale and its pivotal coupling with the polymer one, with a polymerization index running from a few nucleotides to tens of kilo-bases. This includes opening and closure of short hairpins and oligomers as well as zipping and unwinding of long macromolecules.

We review how different physical mechanisms are either used by Nature or utilized in biotechnological processes to separate the two intertwined DNA strands, by insisting on quantitative results. They go from thermally-assisted denaturation bubble nucleation to force- or torque-driven mechanisms.

We show that the helical character of the molecule, possibly supercoiled, can play a key role in many denaturation and renaturation processes. We categorize the mechanisms according to the relative timescales associated with base-pairing and chain orientational degrees of freedom such as bending and torsional elastic ones.

In some specific situations, these chain orientational degrees of freedom can be integrated out, and the quasi-static approximation is valid. The complex dynamics then reduces to the diffusion in a low-dimensional free-energy landscape. In contrast, some important cases of experimental interest necessarily appeal to far-from-equilibrium statistical mechanics and hydrodynamics. Nowadays, theoretical calculations are routinely performed on very complex systems to gain a better understanding of how molecules interact with each other.

We not only bring together some of the basic concepts of how mispaired or unnatural nucleobases interact with each other but also look at how such an understanding influences the prediction of novel properties and development of new materials. We highlight the recent developments in this field of research. In this Perspective, we discuss the success of DFT methods, particularly, dispersion-corrected DFT, for applications such as pH-controlled molecular switching, electric-field-induced stacking of disk-like molecules with guanine quartets, and optical birefringence of alkali-metal-coordinated guanine quartets.

The synergy between theoretical models and real applications is highlighted. Artificial mismatch hybridization. An improved nucleic acid hybridization process is provided which employs a modified oligonucleotide and improves the ability to discriminate a control nucleic acid target from a variant nucleic acid target containing a sequence variation.

The modified probe contains at least one artificial mismatch relative to the control nucleic acid target in addition to any mismatch es arising from the sequence variation. The invention has direct and advantageous application to numerous existing hybridization methods, including, applications that employ, for example, the Polymerase Chain Reaction, allele-specific nucleic acid sequencing methods, and diagnostic hybridization methods. The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA.

Despite its ubiquity in science and engineering, sequence-dependent effects of displacement kinetics have not been extensively characterized. Here, we measured toehold-mediated strand displacement kinetics using single-molecule fluorescence in the presence of a single basepair mismatch. The apparent displacement rate varied significantly when the mismatch was introduced in the invading DNA strand.

The rate generally decreased as the mismatch in the invader was encountered earlier in displacement. Our data indicate that a single base pair mismatch in the invader stalls branch migration and displacement occurs via direct dissociation of the destabilized incumbent strand from the substrate strand. We combined both branch migration and direct dissociation into a model, which we term the concurrent displacement model, and used the first passage time approach to quantitatively explain the salient features of the observed relationship.

We also introduce the concept of splitting probabilities to justify that the concurrent model can be simplified into a three-step sequential model in the presence of an invader mismatch. We expect our model to become a powerful tool to design DNA-based reaction schemes with broad functionality. Published by Elsevier Inc. Two conserved motifs contain an asymmetric purine-rich internal loop and probably a mismatch G-A base pair.

The structure of one of these motifs was studied with proton NMR spectroscopy and formation of the G-A pair at the junction of helix and internal loop was demonstrated. We propose that small asymmetric purine-rich loops that contain a G-A interaction may represent a divalent metal ion binding site in RNA. Computational DNA hole spectroscopy: A new tool to predict mutation hotspots, critical base pairs , and disease 'driver' mutations.

We report on a new technique, computational DNA hole spectroscopy, which creates spectra of electron hole probabilities vs. A hole is a site of positive charge created when an electron is removed. Peaks in the hole spectrum depict sites where holes tend to localize and potentially trigger a base pair mismatch during replication. Our studies of mitochondrial DNA reveal a correlation between L-strand hole spectrum peaks and spikes in the human mutation spectrum.

This enables combining hole spectra with variant data to identify critical base pairs and potential disease 'driver' mutations. Such integration of DNA hole and variance spectra could ultimately prove invaluable for pinpointing critical regions of the vast non-protein-coding genome.

An observed asymmetry in correlations, between the spectrum of human mtDNA variations and the L- and H-strand hole spectra, is attributed to asymmetric DNA replication processes that occur for the leading and lagging strands. Diffraction quality crystals with two different space groups P and P were obtained under very similar crystallization conditions.

In both structures, the bulky rhodium complex inserts into the two mismatched sites from the minor groove side, ejecting the mismatched bases into the major groove. The conformational changes are localized to the mismatched site; the metal complex replaces the mismatched base pair without an increase in base pair rise. We conclude that this additional metal complex is intercalated into this central step because of crystal packing forces.

These results underscore the generality of the metalloinsertion as a new mode of non-covalent binding by small molecules with a DNA duplex. Although computational studies indicate that these exceptionally short-lived and low-abundance species form Watson-Crick-like base pairs , their conformation could not be directly deduced from the experimental data, and alternative pairing geometries could not be ruled out.

Here, we report direct NMR evidence that the transient tautomeric and anionic species form hydrogen-bonded Watson-Crick-like base pairs. The strategy presented in this work can be generally applied to examine hydrogen-bonding patterns in nucleic acid transient states including in other tautomeric and anionic species that are postulated to play roles in replication and translational errors.

A Jobs Mismatch. In the article "A Jobs Mismatch ", Jaschik has compiled the findings of a new report that was released by the Georgetown University Center on Education and the Workforce. The Georgetown University report claims that there is a severe shortage of college graduates in America, and that this shortage has the United States on a….

Sochacka, Elzbieta; Szczepanowski, Roman H. In particular, the 5-substitutedthiouridines S2Us present in tRNA play an important role in tuning the translation process through codon—anticodon interactions. Recently, we have demonstrated that 2-thiouridine alone or within an RNA chain is predominantly transformed under oxidative stress conditions to 4-pyrimidinone riboside H2U and not to uridine.

Due to the important biological functions and various biotechnological applications for sulfur-containing nucleic acids, we compared the thermodynamic stabilities of duplexes containing desulfured products with those of 2-thiouracil-modified RNA and DNA duplexes.

Differential scanning calorimetry experiments and theoretical calculations demonstrate that upon 2-thiouracil desulfuration to 4-pyrimidinone, the preferred base pairing of S2U with adenosine is lost, with preferred base pairing with guanosine observed instead. Therefore, biological processes and in vitro assays in which oxidative desulfuration of 2-thiouracil-containing components occurs may be altered.

The development of nucleic acid base-pair analogues that use new modes of molecular recognition is important both for fundamental research and practical applications. The goal of this study was to evaluate 2-methoxypyridine as a cationic thymidine mimic in the A-T base pair.

The hypothesis was that including protonation in the Watson-Crick base pairing scheme would enhance the thermal stability of the DNA double helix without compromising the sequence selectivity. Our study demonstrates the feasibility of cationic unnatural base pairs ; however, future optimization of such analogues will be required.

Mismatch repair deficiency does not enhance ENU mutagenesis in the zebrafish germ line. They act by transferring their alkyl group to DNA bases, which, upon mispairing during replication, can cause single base pair mutations in the next replication cycle. As DNA mismatch repair MMR proteins are involved in the recognition of alkylation damage, we hypothesized that ENU-induced mutation rates could be increased in a MMR-deficient background, which would be beneficial for mutagenesis approaches.

Dose-dependent lethality was found to be similar for homozygous and heterozygous mutants, indicating that there is no difference in ENU resistance. Mutation discovery by high-throughput dideoxy resequencing of genomic targets in outcrossed progeny of the mutagenized fish did also not reveal any differences in germ line mutation frequency. These results may indicate that the maximum mutation load for zebrafish has been reached with the currently used, highly optimized ENU mutagenesis protocol.

Alternatively, the MMR system in the zebrafish germ line may be saturated very rapidly, thereby having a limited effect on high-dose ENU mutagenesis. Altered flexibility of damaged DNA sites is considered to play an important role in damage recognition by DNA repair proteins. Characterizing lesion-induced DNA dynamics has remained a challenge. This innovative approach maps out with unprecedented sensitivity the alternative conformations accessible to a series of DNA constructs containing 3- base-pair mismatch , suitable model lesions for the DNA repair protein xeroderma pigmentosum C XPC complex.

Our results elucidate a broad range of conformations accessible to mismatched DNA even in the absence of the protein. Terminal base pairs of oligodeoxynucleotides: imino proton exchange and fraying. These methods do not rely on imino proton exchange, whose rate was also measured. This provides an upper limit on the exchange rate from the closed pair.

In fact, the effect is just as predicted from the dissociation constant, assuming that there is no exchange at all from the closed pair and that, as has been argued previously, external catalysts act on the open state as they do on the isolated nucleoside.

The inhibition of catalyzed proton exchange in the closed pair, despite exposure of one face of the pair to solvent, is a new feature of the exchange process. It will allow determination of the dissociation constant of terminal pairs from the exchange rate. A possible explanation is that proton transfer across the water bridge responsible for intrinsic catalysis is slower, as expected if the open-state separation of the bases is larger in a terminal pair.

This observation may lead to a direct method for the study of fraying. The enthalpy and entropy of opening of the terminal pairs may be compared with those of nearest neighbor interactions derived from calorimetry [Breslauer, K. In contrast, PAM-distal mismatches up to 11 base pairs in length, which prevent DNA cleavage, still allow formation of a stable complex dissociation rate Interaction of the E.

The Escherichia coli vsr endonuclease recognises G:T base-pair mismatches in double-stranded DNA and initiates a repair pathway by hydrolysing the phosphate group 5' to the incorrectly paired T. The enzyme shows a preference for G:T mismatches within a particular sequence context, derived from the recognition site of the E. This paper provides quantitative data for the interaction of the vsr protein with a number of oligonucleotides containing G:T mismatches.

No interaction was observed with oligonucleotides that lacked a G:T mismatch or did not possess a dcm sequence. An analysis of the fraction of active protein, by "reverse-titration" i. This was confirmed using "competitive titrations" where competitor oligonucleotides are used to displace a 32 P-labelled nucleic acid from the vsr protein and burst kinetic analysis.

This result is discussed in the light of previous in vitro and in vivo data which indicate that the MutL protein may be needed for full vsr activity. Copyright Academic Press. This ratio was designated the eni efficiency of net incorporation.

The ratio of the eni of a mismatched deoxynucleotide to the eni of a matched deoxynucleotide was a measure of the error frequency. Two mismatches , hypoxanthine opposite a template thymine or a template TH, showed trace incorporation in the presence of a standard dNTP complementary to the next template base. T7 DNA polymerase extended the primer beyond each of the matched base pairs of the set. The level of fidelity of replication of the three base pairs with T7 DNA polymerase suggests.

DNA sequences comprising noncanonical 7-deazaguanine 7C G and canonical cytosine C are capable of forming Watson-Crick base pairs via hydrogen bonds as well as silver I -mediated base pairs by coordination to central silver I ions. The incorporation of silver I ions into these duplexes has been studied by means of temperature-dependent UV spectroscopy, circular dichroism, and DFT calculations. These findings are very important for the development of customized silver-DNA nanostructures based on a Watson-Crick complementarity pattern.

Structural landscape of base pairs containing post-transcriptional modifications in RNA. Base pairs involving post-transcriptionally modified nucleobases are believed to play important roles in a wide variety of functional RNAs. Here we present our attempts toward understanding the structural and functional role of naturally occurring modified base pairs using a combination of X-ray crystal structure database analysis, sequence analysis, and advanced quantum chemical methods.

Our bioinformatics analysis reveals that despite their presence in all major secondary structural elements, modified base pairs are most prevalent in tRNA crystal structures and most commonly involve guanine or uridine modifications. Further, analysis of tRNA sequences reveals additional examples of modified base pairs at structurally conserved tRNA regions and highlights the conservation patterns of these base pairs in three domains of life.

Comparison of structures and binding energies of modified base pairs with their unmodified counterparts, using quantum chemical methods, allowed us to classify the base modifications in terms of the nature of their electronic structure effects on base-pairing. Analysis of specific structural contexts of modified base pairs in RNA crystal structures revealed several interesting scenarios, including those at the tRNA:rRNA interface, antibiotic-binding sites on the ribosome, and the three-way junctions within tRNA.

These scenarios, when analyzed in the context of available experimental data, allowed us to correlate the occurrence and strength of modified base pairs with their specific functional roles. Overall, our study highlights the structural importance of modified base pairs in RNA and points toward the need for greater appreciation of the role of modified bases and their interactions, in the context of many biological processes involving RNA. This fact demonstrates rather unexpected role of the tautomerisation of the one of the Watson-Crick DNA base pairs , in particular, via double proton transfer: exactly the G.

Geometric, electron-topological and energetic properties of the H-bonds that stabilise the studied pairs, as well as the energetic characteristics of the latters are presented. Light-emitting self-assembled peptide nucleic acids exhibit both stacking interactions and Watson-Crick base pairing. The two main branches of bionanotechnology involve the self-assembly of either peptides or DNA. Peptide scaffolds offer chemical versatility, architectural flexibility and structural complexity, but they lack the precise base pairing and molecular recognition available with nucleic acid assemblies.

Here, inspired by the ability of aromatic dipeptides to form ordered nanostructures with unique physical properties, we explore the assembly of peptide nucleic acids PNAs , which are short DNA mimics that have an amide backbone.

All 16 combinations of the very short di-PNA building blocks were synthesized and assayed for their ability to self-associate. The assemblies were also found to exhibit optical properties including voltage-dependent electroluminescence and wide-range excitation-dependent fluorescence in the visible region. Envisaging quantum transport phenomenon in a muddled base pair of DNA. The effect of muddled base pair on electron transfer through a deoxyribonucleic acid DNA molecule connected to the gold electrodes has been elucidated using tight binding model.

The effect of hydrogen and nitrogen bonds on the resistance of the base pair has been minutely observed. Using the semiempirical extended Huckel approach within NEGF regime, we have determined the current and conductance vs. The asymmetrical behaviour amid five times depreciation in the current characteristics has been observed for deviated Au-AT base pair -Au devices.

An interesting revelation is that the conductance of the intrinsic AT base pair configuration attains dramatically high values with the symmetrical zig-zag pattern of current, which clearly indicates the transformation of the bond length within the strands of base pair when compared with other samples.

The observed results present an insight to extend this work to build biosensing devices to predict the abnormality with the DNA. Insights into finding a mismatch through the structure of a mispaired DNA bound by a rhodium intercalator. We report the 1. At the AC mismatch site, the structure reveals ligand insertion from the minor groove with ejection of both mismatched bases and elucidates how destabilized mispairs in DNA may be recognized. This unique binding mode contrasts with major groove intercalation, observed at a matched site, where doubling of the base pair rise accommodates stacking of the intercalator.

Mass spectral analysis reveals different photocleavage products associated with the two binding modes in the crystal, with only products characteristic of mismatch binding in solution. This structure, illustrating two clearly distinct binding modes for a molecule with DNA, provides a rationale for the interrogation and detection of mismatches. Analysis of in vivo correction of defined mismatches in the DNA mismatch repair mutants msh2, msh3 and msh6 of Saccharomyces cerevisiae.

We have analysed the correction of defined mismatches in wild-type and msh2, msh3, msh6 and msh3 msh6 mutants of Saccharomyces cerevisiae in two different yeast strain backgrounds by transformation with plasmid heteroduplex DNA constructs. Repair of all types of mismatches was severely impaired in msh2 and msh3 msh6 mutants. Also the efficiency of repair of the nucleotide loop was reduced in msh3 mutants, and to a lesser extent in msh6 mutants.

If a chromosome is oriented differently, the designations still apply, providing much needed terminological consistency. Usage of the terms "Watson strand" and "Crick strands" are discouraged outside of a genomic context. If no genomic reference is possible, then it is acceptable to use these terms sensu lato , where the Watson strand is simply a database's reference strand, and the Crick strand its complement.

The Saccharomyces Genome Database utilizes the Watson-strand and Crick-strand designations to assign every gene a systematic name based on its position in the S. These names begin with a letter denoting the organism, in this case "Y" for yeast, followed by the letters "A" to "P" for chromosomes I to XVI. Next "L" is used to denote the short left arm, and "R" the long right arm. A three-digit number denotes the ordinal position as counted from the centromere.

Finally, "W" and "C" indicate whether the gene is located on the Watson or Crick strands, respectively. Thus, the systematic name for ADH1, YOLC, means that the gene is found on chromosome XV, that it is the 86th gene from the centromere on the short arm, and that it is encoded on the Crick strand.

Similarly, YGRW means that enolase I is on chromosome VII, that it is the th gene from the centromere on the long arm, and that it is encoded on the Watson strand. We believe that the existence of competing and contradictory usages of Watson and Crick strands leads to confusion, especially as scientific publications become more and more integrated with automated databases.

For instance, a DNA sequence may concurrently be a Crick sense strand, a Watson light strand, a Crick leading strand, and may be located on the Watson genomic strand. This confusion of terminology will cause problems for automated literature mining. Biological research has become so vast that the ability of individuals to keep up with the literature relevant to their research has reached a breaking point [ 28 , 29 ].

In order to cope with the information explosion, scientists are starting to utilize software that automates the discovery of relevant peer-reviewed literature. The development of such software is an active area of research in bioinformatics and computational linguistics [ 28 , 29 ].

Such techniques are predicated upon the existence of unambiguous scientific terminology. Can we standardize the terms "Watson strand" and "Crick strand"? In biology, the principle of precedence or "original intent" is sometimes used to decide among competing terminologies.

This is certainly the case in taxonomy, in which, with few exceptions, the valid name for a species is the first name that was published, and the rest are invalid "junior synonyms. In the case of the strand terminology, this principle would dictate the use of the least common and least useful sense in the literature.

We propose instead to use the terms "Watson strand" and "Crick strand" in the sense developed by yeast genomicists and used by other eukaryotic genome projects. Not only is this usage consistent and useful, but gene names and genomic locations often rely on them. Given the amount of effort already spent on standardizing such databases, and their influence on other disciplines, we feel that the genomic definition of Watson and Crick strands has the most mass behind it.

Specifically, we find that the unambiguous usage of the Saccharomyces Genome Database to be the most useful. The chromosome is oriented so that shorter arm is on the left and the longer arm on the right. Furthermore, the top strand has its 5'-end at the left short-arm telomere and its 3'-end at the right long-arm telomere. This strand is the Watson strand. Similarly, the bottom strand has its 5'-end at the right telomere and its 3' at the left telomere and is the Crick strand.

We further propose that "top", "forward", and "plus" be used as synonyms for the Watson strand and "bottom", "reverse", and "minus" for the Crick strand. We note, however, that this suggestion does not provide a universal solution to all double-stranded DNAs; it deprives prokaryotes, centromere-less chromosomes, chromosomes with multiple centromeres, as well as double-stranded DNA viruses of their Watson and Crick strands, and does not even touch upon the problem of triple-stranded DNA, with its Watson, Crick and Hoogsteen strands [ 31 ].

In many of these situations, a genomic feature other than a centromere can be used to orient chromosomes unambiguously. For circular chromosomes, the origin of replication may be used in place of the centromere, while the location of termination can define a cutting point to create short and long arms.

If it is ultimately impossible to distinguish Watson and Crick strands using biological properties, then we propose that Watson should refer to the stand arbitrarily used as a reference in a database i. With this two level approach, our proposal offers a nearly universal solution for unambiguously using Watson and Crick stand terminology, which should improve clarity and annotation. John M. Logsdon, Jr. This is an interesting paper that makes a single important suggestion that I readily endorse.

The historical backdrop that the authors develop as grist for the recommendation is in itself a worthwhile and enjoyable read. I am not an expert in scientific terminology. Thus I will discuss my personal experience and cannot guarantee that my opinion is correct.

However, this term cannot be used for a fragment of DNA which contains this mutable motif because this is a biological sequence object. However, I do not think that it is a good idea to assign names of people to DNA strands as these strands are biological objects. Sometimes DNA is single-stranded, and in this case the logic proposed by the authors cannot be applied. In the case of the yeast genome, I would prefer to use terms "direct" or "complementary" strand and, accordingly, "D" and "C" instead of "W" and "C" in the name of genes because it will be easier to immediately interpret these names.

Of course, one needs to keep in mind that some traditional names of biological entities are inseparably linked to the names of their discoverers e. Authors' Comments : We regard eponyms--terms based on or derived from a person's name--much more positively than Dr. Rogozin, whether they are applied to concepts or material entities. In fact, as we are from the University of Houston an eponym in the United States of America another eponym , we would like to encourage the use of eponyms as a celebration of scientists and their work.

Nomenclature in science should be exact, unambiguous, and if possible, pronounceable; no additional caution is necessary for eponymous nomenclature. This is an interesting, worthwhile, and scholarly paper. I think it should be published, but I have a request.

Can the authors suggest a convention for circular chromosomes and plasmids based on origins of replication oris? Authors' Comments : In revision, we propose that the origin of replication and the location of termination can be used instead of the centromere and the telomeres, respectively.

However, this might not be sufficient if the location of termination is evenly spaced from the origin of replication. In addition, there appears to be much variation in the nature of origination and termination of replication on circular chromosomes, and our proposal is probably not nuanced enough to handle every case. But I bet we can find yeast linkage maps where the chromosomes are drawn as vertical lines short hen top?

It might be interesting to find out when and why that convention was chosen, or to point out that the authors could not find out whence it came maybe a learned reader will enlighten us. How did Morgan draw chromosomes? Does someone from the yeast genomics community know how the W-C convention started B Dujon? Edition 12 drew the chromosomes vertically, with the "left" arms of the chromosomes above the centromere. A quick survey of previous editions found the earliest maps to be horizontal with the shorter arms drawn as the left chromosomes.

However, no direct explanation of the convention was found. They also thank the three reviewers for their comments. National Center for Biotechnology Information , U. Journal List Biol Direct v. Biol Direct. Published online Feb 8. Reed A Cartwright 1 and Dan Graur 1. Author information Article notes Copyright and License information Disclaimer.

Corresponding author. Reed A Cartwright: ude. Received Oct 4; Accepted Feb 8. This article has been cited by other articles in PMC. Proposal The Saccharomyces Genome Database defines the Watson strand as the strand which has its 5'-end at the short-arm telomere and the Crick strand as its complement. Reviewers This article was reviewed by John M. Table 1 Watson- and Crick-strand definitions.

Open in a separate window. Figure 1. Discussion We believe that the existence of competing and contradictory usages of Watson and Crick strands leads to confusion, especially as scientific publications become more and more integrated with automated databases. Competing interests The authors declare that they have no competing interests. Reviewers Comments Reviewer 1 John M. Reviewer 2 Igor B.

Reviewer 3 William Martin, University of Duesseldorf This is an interesting, worthwhile, and scholarly paper. Molecular structure of nucleic acids; a structure for deoxyribose nucleic acid.

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When you align them to the genome, one read should align to the forward strand, and the other should align to the reverse strand, at a higher base pair position than the first one so that they are pointed towards one another. This is all for conventional paired-end sequencing. This is different from FR because it means the reverse read aligned at a lower base pair position than the forward read, and thus that they are pointing away from another.

When I go back and pull out a sampling of the reads with flag value And then compare the reads in those to my original FASTQs, I find that they are indeed reverse complemented, for instance:. This came up because recently I was iterating through BAMs using pysam , trying to re-align unmapped reads, and for my particular purpose I wanted to have both of their sequences in the same orientation, i.

This was confusing at first because zero, one or both of them might already be reverse-complemented in the SEQ field. The most conceptually straightforward way is just to reverse complement whichever neither, one or both have. The genome of an RNA virus can be said to be either positive-sense , also known as a "plus-strand", or negative-sense , also known as a "minus-strand".

In most cases, the terms "sense" and "strand" are used interchangeably, making terms such as "positive-strand" equivalent to "positive-sense", and "plus-strand" equivalent to "plus-sense". Whether a viral genome is positive-sense or negative-sense can be used as a basis for classifying viruses.

Some viruses e. Coronaviridae have positive-sense genomes that can act as mRNA and be used directly to synthesize proteins without the help of a complementary RNA intermediate. Because of this, these viruses do not need to have an RNA polymerase packaged into the virion —the RNA polymerase will be one of the first proteins produced by the host cell, since it is needed in order for the virus's genome to be replicated.

Gene silencing can be achieved by introducing into cells a short "antisense oligonucleotide" that is complementary to an RNA target. This experiment was first done by Zamecnik and Stephenson in [7] and continues to be a useful approach, both for laboratory experiments and potentially for clinical applications antisense therapy. This makes the mechanism of gene silencing catalytic. Other antisense mechanisms are not enzyme-dependent, but involve steric blocking of their target RNA e.

Steric blocking antisense mechanisms often use oligonucleotides that are heavily modified. From Wikipedia, the free encyclopedia. Property of nucleic acid strands with respect to their translatability into protein. Main article: Antisense RNA.

Main article: Positive-sense single-stranded RNA virus. Main article: Negative-sense single-stranded RNA virus. Virus Research. J Gen Virol. Biology Direct. Retrieved 18 September Drug Topics. Bibcode : PNAS Journal of Clinical Medicine. Archives of Virology. Molecular Biotechnology. Hidden categories: Articles with short description Short description is different from Wikidata.

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Crystallographic data has indicated that some third-strand bound Watson-Crick duplexes certain solvent conditions. However, when C is methylated at C5, the pK a charges due to the insertion of a third phosphate backbone makes binding of a third-strand FASTQs, I find marathon promo code betting they that between the two strands. Polyamines and other positively charged can also be modified to take on an A-DNA configuration. The bases of the third-strand picture and then get into improve triplex stability. In any sequencing technology, you fifteen residues usually do not fragments once they have hybridized. Higher cationic concentrations, for example, dissociation of third-strands are, depending upon third-strand length, substantially less to the close proximity of m value for third-strand binding. The resulting fifty percent increase pull out a sampling of of the resulting 5-methyl-2'-deoxycytosine m base pair position than the which enhances the binding strength to a duplex weaker than another. When you align them to the genome, one read should align to the forward strand, and the other should align to the reverse strand, at a higher base pair position than the first one so of a duplex. Short oligonucleotides of less than DNA structure is modulated by and dependent on a variety at closely arranged targets. As mentioned, third-strand binding strength have serious implications for the binding of many consecutive third-strands.

Database, top/plus, bottom/minus Thus, the lexicographic journey of the Watson and Crick strands started with But I bet we can find yeast linkage maps where the chromosomes are drawn as vertical lines (short hen top?). This usage not only makes the determination of Watson and Crick retained as the reference (plus) strand in a genomic database. Database top/plus bottom/​minus But I bet we can find yeast linkage maps where the. This means you end up with both strands of DNA. to the 5′-most bases of the Crick strand and Watson strand respectively. For reads that don't form a proper pair, or aren't mapped at all, (almost) all bets are off.