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How does bonding between non-complementary bases occur?

How does bonding between non-complementary bases occur?


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My teacher told me that when DNA polymerase makes an error (roughly every 10 million nucleotides?) that if, for example, it matches an A with a G that the error remains and is the main cause of point mutations. How do the two bases that aren't complementary remain bonded?


How do the two bases that aren't complementary remain bonded?

Non complementary bases can only form non-Watson-Crick bonds, which are very unstable and noticeably different.
Therefore any mismatch in the DNA of the genome will form a recognisable disruption of the DNA helix. This disruption is usually removed very quickly by the cells, since it makes DNA much more unstable.

Most cells have multiple mechanisms to detect and repair these sites, with one system specifically dedicated to DNA mismatch repair.
This system acts on mismatches directly after DNA replication, since at this point specific markers (sometimes DNA methylation, sometimes not fully understood) can differentiate between the newly synthesised DNA strand (which may contain an error) and the old one.

The repair mechanism will remove the mismatch and replace it with a properly bonded base pair, so that mismatches in the DNA are always short term issues - it is still possible though that 'wrong' mismatching base is replaced, which then (finally) leads to a mutation.

The error rate of DNA polymerase (1 in 10^7 sounds about right, this is the combination of the initial error rate and the DNA polymerase proof-reading mechansim) therefore has to multiplied with the error rate of this repair mechansim, which is around 10^3 (I can't find a source for this right now), to get a final error rate of DNA replication in cells.


Fidelity of the Replication of DNA | Biochemistry

In this article we will discuss about the fidelity of the replication of DNA.

The DNA being the carrier of genetic information it is essential that this information remains correct. But the DNA can be damaged by the action of chemical or physical agents. The cell therefore possesses repair systems which can maintain the integrity of genetic information.

It is also of utmost importance that during the replication, the newly syn­thesized DNA be an exact copy, correct to one nucleotide, of the template DNA. Replication must therefore be a faithful process i.e. it should make no errors.

If such errors did exist, they could be detected by the repair systems but the latter would not be able to distinguish between the strand carrying the correct information and the one carrying the erroneous information. It is therefore necessary to have a corrector activity during the synthesis.

Corrector Activity of DNA Polymerases:

Given that the genome of E.coli comprises about 4 x 10 6 base pairs, the admissible rate of error for a totally correct replication is one erroneous base for every 10 6 , or even 10 7 , base pairs. The mere complementarity of bases will not ensure such a low rate of error because the bases can tautomerize.

Their enol form (unusual in physiological conditions) can pair with a normally non complementary base: e.g., a cytosine with adenine. It is believed that the frequency of these enolic forms is 10 -4 to 10 -5 base pairs. It may be noted therefore that without a correction mechanism, the fidelity of replication would be 10 -4 or 10 -5 and not 10 -7 .

The correction mechanism was extensively studied in E.coli. It is based on the fact that the DNA polymerases need both a primer and a template. In other words, the polymerase will not be able to bind a new nucleotide to the 3′ OH of a nucleotide not paired to the template DNA. If a base in its enol form has been incorporated, its return to the keto form results in a non-pairing.

Therefore, the DNA polymerase can no longer catalyze the formation of a phosphodiester bond with the following nucleotide. Its 3′ → 5′ exonuclease activity eliminates the ill-paired nucleotide, thus liberating a 3’OH utilizable by the DNA polymerase. A mutation of sub-unit e, carrying the 3′ → 5′ ex­onuclease activity, generates a DNA polymerase III which makes many more errors.

For eucaryotes, the problem of fidelity of replication becomes even more crucial, because the genome of a mammal for example, contains about 3 X 10 9 base pairs. The fidelity of replication must therefore be equal to, or greater than 10 -9 . The existence of an exonuclease activity 3′ → 5′ associated with DNA polymerase d and perhaps with DNA polymerase α explains this fidelity to a large extent.

It is generally admitted that the presence of auxiliary proteins and the very nature of the eucaryote chromosome permit this very low rate of error.

In this sense, it has been observed that the error rate of DNA polymerases increases when the enzymes are in experimental conditions in which they synthesize the DNA in a relatively continuous manner (they are then said to be processive). This suggests that in their active conformation these enzymes are very faithful.

Fidelity and Mechanism of Replication:

As just seen, the fact that a DNA polymerase has an absolute requirement for a primer 3’OH paired with the strand of the template DNA to synthesize a new DNA chain, allows the corrector activity to fully play its role.

It may also be observed that if one of the two strands of the DNA were copied by a DNA polymerase acting in the direction 3′ → 5′ that copy would be less faithful.

As a matter of fact, in this case, the growing chain would carry the triphosphate and the nucleotide to be added would carry the 3’OH. After the hydrolysis of an ill-paired nucleotide, there would be no more triphosphate available on the growing chain to permit the addition of a new nucleotide.

If the first nucleotide incorporated were a deoxyribonucleoside triphos­phate, it could never be corrected by the exonuclease activity. At the end of the synthesis, the ribonucleotide primer will be systematically recognized and eliminated as a result, the fact that the RNA polymerases are not very faithful (10 -4 to 10 -5 ) loses its importance.

One can realize that the very complexity of the replication mechanism (necessity of a primer, synthesis only in the 5′ → 3′ direction, ribonucleic nature of the primer) provides a corrector activity at the precise moment of replication, and sufficient fidelity for maintaining the exact genetic informa­tion.


Complementary Nucleotide Bases

DNA * is the information molecule of the cell. DNA’s capacity to store and transmit heritable information depends on interactions between nucleotide bases and on the fact that some combinations of bases form stable links, while other combinations do not. Base pairs that form stable connections are called complementary bases.

Consistent pairings of complementary bases allow cells to make double-stranded DNA from a single strand template, create messenger RNA from DNA and synthesize proteins from individual amino acids by matching nucleotides bases on messenger RNA with their complementary bases on transfer RNA.

The polynucleotides chains that make up DNA and RNA form via covalent bond * s between sugar and phosphate subunits of neighboring nucleotides along a chain. In addition to the strong covalent bonds that hold polynucleotide chains together, bases along a polynucleotide chain can form hydrogen bonds with bases on other chains (or with bases elsewhere on the same chain, as with secondary structure in RNA).

The formation of stable hydrogen bonds depends on the distance between two strands, the size of the bases and geometry of each base. Stable pairings occur between guanine and cytosine and between adenine and thymine (or adenine and uracil in RNA). Three hydrogen bonds form between guanine and cytosine. Two hydrogen bonds form between adenine and thymine or adenine and uracil.

Complementary pairs always involve one purine and one pyrimidine base * . Pyrimidine-pyrimidine pairings do not occur because these relatively small molecules do not get close enough to form hydrogen bonds. Purine-purine links do not form because these bases are too large to fit in the space between the polynucleotide strands. Asymmetry in the structure of non-complimentary purine - pyrimidine pairs cause some crowding and prevent stable bonds from forming.

Take the concept quiz to test your understanding of complementary nucleotide bases.

Video Overview


What Is Complementary Base Pairing?

Complementary base pairing refers to the structural pairing of nucleotide bases in deoxyribonucleic acid, which is commonly known as DNA. DNA is made up of four nucleotide bases, each of which pairs with only one of the other bases.

The four nucleotide bases in DNA are guanine, cytosine, adenine and thymine. The guanine base is always paired with the complementary cytosine base, and the adenine base is always paired with the complementary thymine base.

A DNA molecule is composed of two connected strands of nucleotide bases, which form a spiraling double helix structure. The two strands of nucleotide bases are arranged such that every base in the first strand is paired to its complementary base in the second strand. Since every nucleotide base is always paired with its complement, you can always deduce the sequence of the second strand if you can identify the sequence of bases in the first strand.

The two sets of complementary base pairs are commonly represented in an abbreviated form that takes the first letter of each base. The guanine-cytosine base pair is represented as G–C, and the adenine-thymine base pair is represented as A–T. In a DNA molecule, the G–C base pair is linked by two hydrogen bonds, and the A–T base pair is linked by three hydrogen bonds.


Nucleic Acids: DNA and RNA

Living organisms are complex systems. Hundreds of thousands of proteins exist inside each one of us to help carry out our daily functions (see our Fats and Proteins module for more information). These proteins are produced locally, assembled piece-by-piece to exact specifications. An enormous amount of information is required to manage this complex system correctly. This information, detailing the specific structure of the proteins inside of our bodies, is stored in a set of molecules called nucleic acids.

The nucleic acids are very large molecules that have two main parts. The backbone of a nucleic acid is made of alternating sugar and phosphate molecules bonded together in a long chain, represented below:

Each of the sugar groups in the backbone is attached (via the bond shown in red) to a third type of molecule called a nucleotide base:

Though only four different nucleotide bases can occur in a nucleic acid, each nucleic acid contains millions of bases bonded to it. The order in which these nucleotide bases appear in the nucleic acid is the coding for the information carried in the molecule. In other words, the nucleotide bases serve as a sort of genetic alphabet on which the structure of each protein in our bodies is encoded.

In most living organisms (except for viruses), genetic information is stored in the molecule deoxyribonucleic acid, or DNA. DNA is made and resides in the nucleus of living cells. DNA gets its name from the sugar molecule contained in its backbone(deoxyribose) however, it gets its significance from its unique structure. Four different nucleotide bases occur in DNA: adenine (A), cytosine (C), guanine (G), and thymine (T).

Interactive Animation:Chemical Structure of the DNA Nucleotides

These nucleotides bind to the sugar backbone of the molecule as follows:

The versatility of DNA comes from the fact that the molecule is actually double-stranded. The nucleotide bases of the DNA molecule form complementary pairs: The nucleotides hydrogen bond to another nucleotide base in a strand of DNA opposite to the original. This bonding is specific, and adenine always bonds to thymine (and vice versa) and guanine always bonds to cytosine (and vice versa). This bonding occurs across the molecule, leading to a double-stranded system as pictured below:

sugar phosphate sugar phosphate sugar phosphate sugar .
T A C G
¦ ¦ ¦ ¦
A T G C
sugar phosphate sugar phosphate sugar phosphate sugar .


In the early 1950s, four scientists, James Watson and Francis Crick at Cambridge University and Maurice Wilkins and Rosalind Franklin at King's College, determined the true structure of DNA from data and X-ray pictures of the molecule that Franklin had taken. In 1953, Watson and Crick published a paper in the scientific journal Nature describing this research. Watson, Crick, Wilkins and Franklin had shown that not only is the DNA molecule double-stranded, but the two strands wrap around each other forming a coil, or helix. The true structure of the DNA molecule is a double helix, as shown at right.

The double-stranded DNA molecule has the unique ability that it can make exact copies of itself, or self-replicate. When more DNA is required by an organism (such as during reproduction or cell growth) the hydrogen bonds between the nucleotide bases break and the two single strands of DNA separate. New complementary bases are brought in by the cell and paired up with each of the two separate strands, thus forming two new, identical, double-stranded DNA molecules. This concept is illustrated in the animation below.

Interactive Animation: The Replication of DNA

Ribonucleic acid, or RNA, gets its name from the sugar group in the molecule's backbone - ribose. Several important similarities and differences exist between RNA and DNA. Like DNA, RNA has a sugar-phosphate backbone with nucleotide bases attached to it. Like DNA, RNA contains the bases adenine (A), cytosine (C), and guanine (G) however, RNA does not contain thymine, instead, RNA's fourth nucleotide is the base uracil (U). Unlike the double-stranded DNA molecule, RNA is a single-stranded molecule. RNA is the main genetic material used in the organisms called viruses, and RNA is also important in the production of proteins in other living organisms. RNA can move around the cells of living organisms and thus serves as a sort of genetic messenger, relaying the information stored in the cell's DNA out from the nucleus to other parts of the cell where it is used to help make proteins.


DNA Damage and Repair

We generally accept the notion that replication duplicates genetic material faithfully. At the same time, evolution would not be possible without mutations, and mutations are not possible without at least some adverse consequences.

Since the complex chemistry of replication is subject to errors, cells have evolved systems of DNA repair to survive and fix mutations. As we saw, DNA polymerases have proofreading ability so that incorrectly inserted nucleotides in the daughter strand can be quickly removed by exonuclease activity and repaired using the parent strand by the polymerase itself. Beyond this, multiple mechanisms have evolved to repair mismatched base pairs and other kinds of damaged DNA that escape early detection. For small mutations (single point mutations) the strand without the mutation will be used to help repair the DNA. For larger mutations (large deletions or breaks in the backbone), a homologous strand of DNA is often used to help repair the damage. How often and where DNA damage occurs is random, as is which damage will be repaired and which will escape detection to become a mutation.


DNA polymerase can make mistakes while adding nucleotides. It edits the DNA by proofreading every newly added base. Incorrect bases are removed and replaced by the correct base, and then polymerization continues (Figure 3a). Most mistakes are corrected during replication, although when this does not happen, the mismatch repair mechanism is employed. Mismatch repair enzymes recognize the wrongly incorporated base and excise it from the DNA, replacing it with the correct base (Figure 3b). In yet another type of repair, nucleotide excision repair, the DNA double strand is unwound and separated, the incorrect bases are removed along with a few bases on the 5′ and 3′ end, and these are replaced by copying the template with the help of DNA polymerase (Figure 3c). Nucleotide excision repair is particularly important in correcting thymine dimers, which are primarily caused by ultraviolet light. In a thymine dimer, two thymine nucleotides adjacent to each other on one strand are covalently bonded to each other rather than their complementary bases. If the dimer is not removed and repaired it will lead to a mutation. Individuals with flaws in their nucleotide excision repair genes show extreme sensitivity to sunlight and develop skin cancers early in life.

Figure 3. Proofreading by DNA polymerase (a) corrects errors during replication. In mismatch repair (b), the incorrectly added base is detected after replication. The mismatch repair proteins detect this base and remove it from the newly synthesized strand by nuclease action. The gap is now filled with the correctly paired base. Nucleotide excision (c) repairs thymine dimers. When exposed to UV, thymines lying adjacent to each other can form thymine dimers. In normal cells, they are excised and replaced.

Most mistakes are corrected if they are not, they may result in a mutation—defined as a permanent change in the DNA sequence. Mutations in repair genes may lead to serious consequences like cancer.


Applications for Hydrogen Bonds

Hydrogen bonds occur in inorganic molecules, such as water, and organic molecules, such as DNA and proteins. The two complementary strands of DNA are held together by hydrogen bonds between complementary nucleotides (A&T, C&G). Hydrogen bonding in water contributes to its unique properties, including its high boiling point (100 °C) and surface tension.

Figure (PageIndex<1>): Water droplets on a leaf: The hydrogen bonds formed between water molecules in water droplets are stronger than the other intermolecular forces between the water molecules and the leaf, contributing to high surface tension and distinct water droplets.

In biology, intramolecular hydrogen bonding is partly responsible for the secondary, tertiary, and quaternary structures of proteins and nucleic acids. The hydrogen bonds help the proteins and nucleic acids form and maintain specific shapes.


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Base pair

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Base pair, in molecular biology, two complementary nitrogenous molecules that are connected by hydrogen bonds. Base pairs are found in double-stranded DNA and RNA, where the bonds between them connect the two strands, making the double-stranded structures possible. Base pairs themselves are formed from bases, which are complementary nitrogen-rich organic compounds known as purines or pyrimidines. According to Watson-Crick base-pairing, which forms the basis for the helical configuration of double-stranded DNA, DNA contains four bases: the two purines adenine (A) and guanine (G) and the two pyrimidines cytosine (C) and thymine (T). Within the DNA molecule, A bonds only with T and C bonds only with G. In RNA, thymine is replaced by uracil (U). Non-Watson-Crick base-pairing models display alternative hydrogen-bonding patterns examples are Hoogsteen base pairs, which are A-T or C-G analogues.

Base pairs often are used to measure the size of an individual gene within a DNA molecule. The total number of base pairs is equal to the number of nucleotides in one of the strands (each nucleotide consists of a base pair, a deoxyribose sugar, and a phosphate group). With extremely complex genomes, the detailing of base pairs can be complicated. The human genome, for example, is made up of an estimated three billion base pairs, with about 20,000 to 25,000 distinct genes. For dealing with those large numbers, scientists use measures such as kilobase pair (kb, or kbp), which is equivalent to 1,000 base pairs megabase pair (Mb), which is equivalent to one million base pairs and gigabase pair (Gb), which is equivalent to one billion base pairs.



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