Correlations and helical coherence in dna structure

Correlations and helical coherence in dna structure

It is a left-handed double helical structure in which the helix winds to the left in a zigzag pattern, instead of to the right, like the more common B-DNA form. Left-handed DNA was first discovered by Robert Wells and colleagues, during their studies of a repeating polymer of inosine — cytosine. It was resolved as a left-handed double helix with two antiparallel chains that were held together by Watson—Crick base pairs see X-ray crystallography.

It was solved by Andrew H.

Z-DNA is quite different from the right-handed forms. The Z-DNA helix is left-handed and has a structure that repeats every other base pair. Instead, it is a transient structure that is occasionally induced by biological activity and then quickly disappears. Shing Ho in at MIT. This result coincides with the computational results of Lee et al.

To showcase this, a study was conducted on the DNA found in the hippocampus of brains that were normal, moderately affected with Alzheimer's disease, and severely affected with Alzheimer's disease.

Through radioimmunoassay, it was found that one interacts with the bases exposed on the surface of Z-DNA and denatured DNA, while the other exclusively interacts with the zig-zag backbone of only Z-DNA. Similar to that found in Alzheimer's disease, the antibodies vary depending on the stage of the disease, with maximal antibodies in the most active stages of SLE.

Z-DNA is commonly believed to provide torsional strain relief during transcriptionand it is associated with negative supercoiling. A study of human chromosome 22 showed a correlation between Z-DNA forming regions and promoter regions for nuclear factor I. This suggests that transcription in some human genes may be regulated by Z-DNA formation and nuclear factor I activation. Z-DNA sequences downstream of promoter regions have been shown to stimulate transcription.

The greatest increase in activity is observed when the Z-DNA sequence is placed three helical turns after the promoter sequence. Because of this property, Z-DNA is hypothesized to code for nucleosome positioning. Since the placement of nucleosomes influences the binding of transcription factorsZ-DNA is thought to regulate the rate of transcription. Developed behind the pathway of RNA polymerase through negative supercoiling, Z-DNA formed via active transcription has been shown to increase genetic instability, creating a propensity towards mutagenesis near promoters.

Both of these genetic modifications have been linked to the gene translocations found in cancers such as leukemia and lymphomasince breakage regions in tumor cells have been plotted around Z-DNA-forming sequences. Two critical components to the E3L protein that determine virulence are the N-terminus and the C-terminus.

This supports their claim that the N-terminus containing the Z-DNA binding residues is necessary for virulence. A future implication of these findings includes reducing Z-DNA binding of E3L in vaccines containing the vaccinia virus so negative reactions to the virus can be minimized in humans. From Wikipedia, the free encyclopedia.Aaron Wynveen, Dominic J. Lee, Alexei A. The twist, rise, slide, shift, tilt and roll between adjoining base pairs in DNA depend on the identity of the bases.

The resulting dependence of the double helix conformation on the nucleotide sequence is important for DNA recognition by proteins, packaging and maintenance of genetic material, and other interactions involving DNA. This dependence, however, is obscured by poorly understood variations in the stacking geometry of the same adjoining base pairs within different sequence contexts. We evaluate the corresponding helical coherence length —a cumulative parameter quantifying sequence-dependent deviations from the ideal double helix geometry.

We find, e. Packing of oligomers in crystals dramatically alters their helical coherence. Sequence dependence of the double helix structure and elasticity appear to play an important role in many fundamental processes involving DNA. X-ray and NMR structures of DNA oligomers reveal that the sequence affects the twist, rise, roll, tilt and other parameters characterizing the conformation of adjoining base pairs within the double helix base pair step parameters 1—5.

The resulting intrinsic preference of the double helix to bend and twist at certain sequences may be important, e.

Undulations enhance the effect of helical structure on DNA interactions

The actual twisting, stretching and bending of the double helix hereafter referred to as the DNA conformation may not only reflect the tendency of the base pairs to stack at distances and angles dependent on their identity but may also depend on interactions with other molecules. The conformation of DNA may also depend on other environmental factors, e. Analysis of how the DNA conformation depends on the nucleotide sequence is complicated by variations in the stacking geometry of the base pairs at each specific step with the surrounding sequence 18— This dependence of the base pair step parameters on the sequence context is not only poorly understood but is sometimes left unnoticed.

In other words, the sequence-dependent DNA conformation may both affect and be affected by the DNA environment and function. One approach to understanding these structure—function relationships is through computer simulations that explicitly account for each base pair, e. This approach, however, is limited by our knowledge of microscopic interaction potentials and by other inherent restrictions and assumptions.

Another approach is through relating important DNA properties to cumulative statistical parameters rather than to conformations of individual base pair steps.

So far this approach has been limited primarily to a simplified elastic rod model of DNA 102125— For instance, bending of the central axis of DNA has been described by the bending elasticity modulus and bending persistence length. Twisting of DNA has been described by the torsional elasticity modulus and the corresponding persistence length.Vibronic coupling between pigment molecules is believed to prolong coherences in photosynthetic pigment—protein complexes.

Reproducing long-lived coherences using vibronically coupled chromophores in synthetic DNA constructs presents a biomimetic route to efficient artificial light harvesting. Here, we present two-dimensional 2D electronic spectra of one monomeric Cy5 construct and two dimeric Cy5 constructs 0 bp and 1 bp between dyes on a DNA scaffold and perform beating frequency analysis to interpret observed coherences.

Power spectra of quantum beating signals of the dimers reveal high frequency oscillations that correspond to coherences between vibronic exciton states. Our observations are well described by a vibronic exciton model, which predicts the excitonic coupling strength in the dimers and the resulting molecular exciton states.

The energy spacing between those states closely corresponds to the observed beat frequencies. MD simulations indicate that the dyes in our constructs lie largely internal to the DNA base stacking region, similar to the native design of biological light harvesting complexes.

Helical coherence of DNA in crystals and solution

Observed coherences persist on the timescale of photosynthetic energy transfer yielding further parallels to observed biological coherences, establishing DNA as an attractive scaffold for synthetic light harvesting applications. Material from this article can be used in other publications provided that the correct acknowledgement is given with the reproduced material and it is not used for commercial purposes.

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Pick and Choose.A major landmark was attained in when American geneticist and biophysicist James D. Their breakthrough was made possible by the work of British scientist Rosalind Franklinwhose X-ray diffraction studies of the DNA molecule shed light on its helical structure. The double helix model showed that DNA was capable of self-replication by separating its complementary strands and using them as templates for the synthesis of new DNA molecules.

Each of the intertwined strands of DNA was proposed to be a chain of chemical groups called nucleotide s, of which there were known to be four types. Because proteins are strings of amino acid s, it was proposed that a specific nucleotide sequence of DNA could contain a code for an amino acid sequence and hence protein structure. In American molecular biologist Seymour Benzerextending earlier studies in Drosophilashowed that the mutant sites within a gene could be mapped in relation to each other.

His linear map indicated that the gene itself is a linear structure. In the strand-separation method for DNA replication called the semiconservative method was demonstrated experimentally for the first time by American molecular biologist Matthew Meselson and American geneticist Franklin W. In Crick and South African biologist Sydney Brenner showed that the genetic code must be read in triplets of nucleotides, called codons. American geneticist Charles Yanofsky showed that the positions of mutant sites within a gene matched perfectly the positions of altered amino acids in the amino acid sequence of the corresponding protein.

In the complete genetic code of all 64 possible triplet coding units codonsand the specific amino acids they code for, was deduced by American biochemists Marshall Nirenberg and Har Gobind Khorana. Subsequent studies in many organisms showed that the double helical structure of DNA, the mode of its replication, and the genetic code are the same in virtually all organisms, including plant s, animal s, fungibacteriaand virus es.

Technical advances have played an important role in the advance of genetic understanding. In American microbiologists Daniel Nathans and Hamilton Othanel Smith discovered a specialized class of enzymes called restriction enzymes that cut DNA at specific nucleotide target sequences.

That discovery allowed American biochemist Paul Berg in the early s to make the first artificial recombinant DNA molecule by isolating DNA molecules from different sources, cutting them, and joining them together in a test tube. Shortly thereafter, American biochemists Herbert W. Boyer and Stanley N. Cohen came up with methods to produce recombinant plasmids extragenomic circular DNA elementswhich replicated naturally when inserted into bacterial cells.

These advances allowed individual genes to be cloned amplified to a high copy number by splicing them into self-replicating DNA molecules, such as plasmids or viruses, and inserting these into living bacterial cells. From these methodologies arose the field of recombinant DNA technology that came to dominate molecular genetics.

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In two different methods were invented for determining the nucleotide sequence of DNA: one by American molecular biologists Allan Maxam and Walter Gilbert and the other by English biochemist Fred Sanger. Such technologies made it possible to examine the structure of genes directly by nucleotide sequencing, resulting in the confirmation of many of the inferences about genes originally made indirectly.

In the s Canadian biochemist Michael Smith revolutionized the art of redesigning genes by devising a method for inducing specifically tailored mutations at defined sites within a gene, creating a technique known as site-directed mutagenesis.

In American biochemist Kary B. Mullis invented the polymerase chain reactiona method for rapidly detecting and amplifying a specific DNA sequence without cloning it.The twist, rise, slide, shift, tilt and roll between adjoining base pairs in DNA depend on the identity of the bases.

The resulting dependence of the double helix conformation on the nucleotide sequence is important for DNA recognition by proteins, packaging and maintenance of genetic material, and other interactions involving DNA. This dependence, however, is obscured by poorly understood variations in the stacking geometry of the same adjoining base pairs within different sequence contexts.

We evaluate the corresponding helical coherence length —a cumulative parameter quantifying sequence-dependent deviations from the ideal double helix geometry.

We find, e.

correlations and helical coherence in dna structure

Packing of oligomers in crystals dramatically alters their helical coherence. Sequence dependence of the double helix structure and elasticity appear to play an important role in many fundamental processes involving DNA. X-ray and NMR structures of DNA oligomers reveal that the sequence affects the twist, rise, roll, tilt and other parameters characterizing the conformation of adjoining base pairs within the double helix base pair step parameters 1—5.

The resulting intrinsic preference of the double helix to bend and twist at certain sequences may be important, e. The actual twisting, stretching and bending of the double helix hereafter referred to as the DNA conformation may not only reflect the tendency of the base pairs to stack at distances and angles dependent on their identity but may also depend on interactions with other molecules.

The conformation of DNA may also depend on other environmental factors, e. Analysis of how the DNA conformation depends on the nucleotide sequence is complicated by variations in the stacking geometry of the base pairs at each specific step with the surrounding sequence 18— This dependence of the base pair step parameters on the sequence context is not only poorly understood but is sometimes left unnoticed.

In other words, the sequence-dependent DNA conformation may both affect and be affected by the DNA environment and function. One approach to understanding these structure—function relationships is through computer simulations that explicitly account for each base pair, e. This approach, however, is limited by our knowledge of microscopic interaction potentials and by other inherent restrictions and assumptions.

Another approach is through relating important DNA properties to cumulative statistical parameters rather than to conformations of individual base pair steps. So far this approach has been limited primarily to a simplified elastic rod model of DNA 102125— For instance, bending of the central axis of DNA has been described by the bending elasticity modulus and bending persistence length.

Twisting of DNA has been described by the torsional elasticity modulus and the corresponding persistence length. These parameters have proved to be very useful in characterizing a number of DNA properties and interactions 25—28but they contain no information about the helical conformation of the molecule and its sequence.

Nuclear magnetic resonance spectroscopy of nucleic acids

To incorporate cumulative parameters of the sequence-dependent helical structure into the latter approach, we proposed to describe sequence and thermal variations in the twist between adjoining base pairs with the twist coherence length 29— This length characterizes the ability of DNA to follow a structure close to a geometrically perfect double helix in the same way as the bending persistence length characterizes the ability of DNA centerline to follow a straight line Figure 1. Schematic illustration of non-ideal helical geometry and helical coherence of straight DNA.

Since twist and rise variations at each base pair step are small, these molecules remain close to the ideal helical alignment over many steps. However, accumulating twist and rise displacements eventually disrupt their alignment. The helical phase of each DNA is determined by its sequence, as illustrated by the plot. The helical coherence length is the axial distance at which this mean-square displacement exceeds 1 rad 2.During the last decade, theory and experiments have provided clear evidence that specific helical patterns of charged groups and adsorbed condensed counterions on the DNA surface are responsible for many important features of DNA-DNA interactions in hydrated aggregates.

The effects of helical structure on DNA-DNA interactions result from a preferential juxtaposition of the negatively charged sugar phosphate backbone with counterions bound within the grooves of the opposing molecule. Analysis of x-ray diffraction experiments confirmed the mutual alignment of parallel molecules in hydrated aggregates required for such juxtaposition.

correlations and helical coherence in dna structure

However, it remained unclear how this alignment and molecular interactions might be affected by intrinsic and thermal fluctuations, which cause structural deviations away from an ideal double helical conformation.

We previously argued that the torsional flexibility of DNA allows the molecules to adapt their structure to accommodate a more electrostatically favorable alignment between molecules, partially compensating disruptive fluctuation effects.

In the present work, we develop a more comprehensive theory, incorporating also stretching and bending fluctuations of DNA. We found the effects of stretching to be qualitatively and quantitatively similar to those of twisting fluctuations. However, this theory predicts more dramatic and surprising effects of bending.

Undulations of DNA in hydrated aggregates strongly amplify rather than weaken the helical structure effects. They enhance the structural adaptation, leading to better alignment of neighboring molecules and pushing the geometry of the DNA backbone closer to that of an ideal helix. These predictions are supported by a quantitative comparison of the calculated and measured osmotic pressures in DNA.

They could also play an important role in genetic recombination 8910 Because DNA is highly charged, it was presumed from early on that interactions between DNA double helices should be dominated by electrostatics 1213 Forces measured between DNA double helices were indeed found to be consistent with electrostatic interactions predicted for worm-like, homogeneously-charged chains, but not in the last 2 nm of surface-to-surface separation 15 Because the latter distance range is the one most relevant for biology and the one in which the most interesting phenomena are observed, interpretations of these forces are still hotly debated 17 In a review of different theories and experiments, we argued that the short-range forces between DNA molecules are of electrostatic origin A rigorous theory of electrostatic DNA-DNA interactions must account not only for the net charge of the molecules but also for the helical patterning of fixed molecular charges, preferential binding and the resultant patterning of counterions, and thermal fluctuations and correlations in these charge patterns 18 These resulting interactions between DNA molecules may be crudely separated into three components.

The net charge of the molecule leads to net-charge repulsionwhich may be approximated as an interaction between homogeneously charged cylinders. Discrete patterns of phosphate and counterion charges lead to image-charge repulsion from dielectric cores of neighboring molecules, which is severely underestimated and often omitted in homogeneously-charged cylinder approximations 20 Correlated alignment of positive and negative charges on opposing surfaces results in an attractive electrostatic force.

correlations and helical coherence in dna structure

This attraction is particularly salient in cases of biologically important, polyvalent counterions such as spermine and spermidine that exhibit strong preferential binding in the major groove of DNA 18 A theory of interactions between ideal, rigid, DNA-like helices predicted that electrostatic zipper attraction and image-charge repulsion may be important for many observed phenomena.

For instance, they may contribute to DNA condensation by counterions 182023the B -to- A transition in dense DNA aggregates 24and the formation of the cholesteric phase in more hydrated aggregates 252627 However, real DNA molecules are neither ideal nor rigid helices. They twist, stretch, and bend because of sequence-dependent variations in the geometry of base pair stacking 29and because of thermal motions 3031 These intrinsic and thermal fluctuations in the double helix structure may affect DNA-DNA interactions, for instance, by disrupting the energetically favorable zipper alignment.

Conversely, the interactions may suppress the fluctuations and induce an adaptation of the molecular structure towards a more favorable alignment. Calculations of twisting fluctuations and torsional adaptation have revealed a complex balance of forces, geometry, and motion, which cannot be neglected 3334 In particular, the sequence-dependent intrinsic fluctuations may be responsible for sequence homology recognition between intact, double helical molecules 1036 Full understanding of the balance among DNA structure, flexibility, fluctuations and interactions requires a comprehensive statistical-mechanical theory, in which all of these factors are treated on the same footing.

So far, only twisting fluctuations were analyzed in this context 34 We argued that stretching fluctuations should affect interactions between DNA molecules in the same way as twisting, but this was not rigorously proven The molecular structure of the DNA double helix has been known for 60 years, but we remain surprisingly ignorant of the balance of forces that determine its mechanical properties.

The DNA double helix is among the stiffest of all biopolymers, but neither theory nor experiment has provided a coherent understanding of the relative roles of attractive base stacking forces and repulsive electrostatic forces creating this stiffness. To gain insight, we have created a family of double-helical DNA-like polymers where one of the four normal bases is replaced with various cationic, anionic or neutral analogs. We apply DNA ligase-catalyzed cyclization kinetics experiments to measure the bending and twisting flexibilities of these polymers under low salt conditions.

We suggest that rather than modifying DNA stiffness through a mechanism easily interpretable as electrostatic, the more dominant effect of neutral and charged base modifications is their ability to drive transitions to helical conformations different from canonical B-form DNA. Double-helical DNA has unique attributes including its high thermal stability, high negative charge density and strong resistance to both bending and twisting.

The impact of sequence on DNA mechanical properties has been well studied 3. However, the relationship between stacking characteristics and bending mechanics is not straightforward.

Clearly, local dimer step conformational flexibility in crystallography is not the same as global mechanical bending flexibility. The thermal stability of double-helical DNA involves pairing of complementary bases and stacking of adjacent base pairs 10yet it remains unclear if these base interactions play the dominant role in DNA bend and twist stiffness, as repulsive forces between negatively charged backbone phosphodiester linkages have also been implicated in conferring DNA mechanical rigidity through electrostatic tension Thus, why different DNA sequences have different mechanical properties is unknown.

Theoretical models for the origin of DNA stiffness show no consensus, with the role of electrostatic effects ranging from negligible to dominant. For example, by applying a uniform charge density to the WLC model for suitably long DNAs, Odijk-Skolnick-Fixman theory 1213 separated the persistence length of DNA into two additive components, one electrostatic and one inherent nonelectrostatic.

In this theory, the electrostatic component plays a relatively minor role in overall DNA stiffness. Other attempts have been made to augment the existing WLC theory for cyclization with an electrostatic component based on counterion condensation CC This theory predicts a striking electrostatic contribution to DNA stiffness at low salt, but a much smaller contribution under physiological conditions.

Toward the middle of the spectrum, recent all-atom and course-grained molecular dynamics simulations predict a significant contribution of electrostatic forces to DNA stiffness, comparable with that of nonelectrostatic interactions Other calculations suggest that electrostatic forces make a substantial contribution to the energetics opposing the bending of fully charged DNAs into small circles Counterion distributions in the DNA grooves have also been suggested as important electrostatic modulators determining local DNA mechanics 17— Thus, the relative contributions of base stacking and electrostatic tension to DNA rigidity continue to be debated theoretically.

It is challenging to experimentally isolate the roles of nonelectrostatic stiffening forces including base pair stacking from electrostatic forces. This molecule was shown to be much more flexible than the equivalent full duplex, but the flexibility returned to normal on addition of complementary free purine bases, suggesting that base pair stacking is the dominant contributor to DNA stiffness On the other hand, laterally asymmetric modification of DNA charge induces DNA bending in both experiments and simulations, supporting a role for electrostatic effects in DNA mechanics 21— Here we present an unbiased experimental approach to explore the origins of the mechanical properties of DNA-like polymers.

We synthesized eight DNA-like duplexes with chemical modifications that preserve base pairing while decorating the DNA grooves to alter charge, base stacking or both Figure 1 A. We then characterized the polymers and measured the bend and twist stiffness of each using ligase-catalyzed cyclization kinetics experiments Figure 1 C. Experimental design. Three-dimensional structure of B-form DNA The central stacked DNA base pairs and deoxyribose sugars are uncharged cyanwhile each phosphodiester linkage carries a negative charge gray.

correlations and helical coherence in dna structure

Seven of the eight tested base modifications replace the methyl group red of thymine bases in the DNA major groove, while one modification replaces the N 2 proton blue of adenine bases in the DNA minor groove. Base modifications occur either at the 5 position of thymine compare 1 with 2 - 8 or the 2 position of adenine 9.

Based on the p K a values of the isolated functional groups, modifications 46and 8 alter DNA charge at neutral pH. The readout of these experiments is a ring closure probability J -factorwhich can be interpreted using the WLC model to estimate DNA mechanical parameters. To generate DNA where only one strand contained analog 8the previous conditions were modified so that the template was replaced with the desired amount of unmodified PCR product and the number of cycles was reduced from 30 to a single extension cycle.

The chromatography was monitored with a ultraviolet detector at nm and a conductivity meter. Limitations and assumptions of the model are detailed in Supplementary Data S2. To eliminate the effects of potential binding affinity differences of the dye, each experiment was performed in triplicate for a given dye concentration, and dye-free values of the parameters were determined by linear extrapolation to zero dye concentration.

Circular dichroism CD spectroscopy was performed using a J spectropolarimeter Jasco. Briefly, ultraviolet-CD spectra were acquired from — nm, taking measurements every 0. Samples were monitored five times with the average of the five scans reported.


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