The Miracle Molecule :: DNA
DNA - The Miracle Molecule
At the heart of genetics is DNA (Deoxy-riboNucleic Acid) - the long, twisted, helical and ladder-like molecule of several elements, called nucleotides, joined in two complementary, antiparallel strands i.e. one strand runs from 5'- terminal (determined by the fifth carbon of a free nucleotide) to 3'- terminal (the third unoccupied carbon of a nucleotide) and vice versa, connected by “weak” bonds between two nitrogenous bases. There are five such bases:- Adenine (A), Thymine (T), Cytosine (C), Guanine (G) and Uracil (U).
Based on their skeletal structure, these bases are grouped into two types:- (i) Purines (Adenine and Guanine) and (ii) Pyrimidines (Cytosine, Thymine and Uracil). This particular set of nitrogenous bases provides for the optimal balance of stability and efficiency of transmission of hereditary information. Each of these nitrogenous bases, in the presence of a sugar, called deoxyribose, and a phosphate group, contributed by small amounts of phosphoric acid, together form a nucleotide. The absence of a phosphate group forms a nucleoside.
The different types of nitrogenous bases in DNA and RNA
A small exercise for the readers .... Spot the Difference between T and U
Well done ... an extra bond line .... the presence of an extra methyl (—CH3) group makes T a more stable analogue of U. Hence we see Thymine in DNA and not Uracil.
🤔 Preferential Partnering - at the basic gene level ??
Now, when we see the structure of DNA, we observe that adenine always pairs with thymine and cytosine always pairs with guanine.
Well, there are two main reasons for that.
Reason 1
The first, and most significant, reason is the presence of those "weak" bonds, specifically hydrogen bonds, which only exist between hydrogen atoms and highly reactive atoms, such as fluorine, nitrogen and oxygen. The structures of the nitrogenous bases are such that purines can only bond with pyrimidines due to compatible H- bonding i.e. they can easily form H- bonds.
The more such bonds that exist between two molecules, the more stable the overall helical structure of DNA, hence adenine pairs specifically with thymine and cytosine with guanine. This also results in complementarity of the two DNA strands. We must keep in mind that each strand of DNA is antiparallel i.e. they run in the opposite directions to each other. One strand runs from 5' end to 3' end and the other one from 3' to 5'-end. Here, 5'- end refers to that end where the fifth carbon is not attached to a nucleotide and likewise for 3'- end, albeit the 3'- end has a free hydroxyl (-OH) group.
🤔 Why Weak Bonds (and not Strong bonds) ??
When we come across the process of transcription, we will see that the helix needs to be broken into two strands in order to carry out the process of making the proteins, which are vital for our basic functions. Then, to break stronger bonds will be highly inefficient and energy-consuming for our body. It may be very tiny amounts of energy per cell, but remember that we are made of trillions of cells. Cumulatively, it will be a substantial amount of energy lost. In contrast, weaker bonds allow the easy splitting of the two strands, while cumulatively providing just about enough to keep the DNA molecule highly stable.
Reason 2
The second reason is to maintain the bond length in between the two strands, hence maintaining uniformity in 'each step of the ladder', allowing for stability of the complex helical structure of DNA.
We know that the purine and pyrimidine groups of nitrogenous bases have different skeletal structures, and that bonding between two purines or two pyrimidines is not possible.
Now, suppose that, hypothetically, adenine was to bind with guanine and thymine with cytosine. From the structures in the image, it would be possible to imagine a structure having one extremely short, powerful bond (between thymine and cytosine) and one extremely long, weak bond (between adenine and guanine). This results in uneven bonds, which produces stress on the 'ladder', possibly 'breaking' it.
🤔 Why is 'T' present in DNA and not 'U'?
As we have seen before, Thymine (T) is more stable than Uracil (U), due to the presence of a methyl group in Thymine. This extra stability leads to an increase in the stability of DNA over RNA, which results in a lower rate of changes i.e. mutations occurring in the DNA molecule. This change is favourable for larger multicellular organisms, to allow for a more controlled process of evolution, as compared to the randomly occurring mutations in RNA-based organisms.
The Rise of a New Generation of DNA
We know that each cell in our body has an expiry date, much like any daily product that we use. But it is essential for our very existence and our defining traits.
So when a cell dies, does that mean we lose the genetic material corresponding to that cell?
Well, fear not, just like how our cells replenish themselves by dividing into multiple clones of themselves, even our DNA clones itself, with a twist - DNA doesnt clone from the lost one .. Instead, it forms very similar copies of itself, with a few variations to ensure adaptability to the surrounding conditions.
This model was demonstrated by two scientists, Matthew Meselson and Franklin Stahl, by using the DNA of "Escherichia coli". A colony of "E.coli" bacteria was grown on a culture (nutrition) medium containing a heavy isotope (atom of the same atomic number but a different atomic weight) of nitrogen (N- 15 i.e. nitrogen of atomic weight 15 a.m.u; the most common isotope has an atomic weight of 14 a.m.u), in the form of a common fertiliser, ammonium chloride. It was observed that the heavy isotope of nitrogen was easily incorporated into the DNA strands of the bacteria, leading to the formation of hybrid DNA strands (one heavy, newly formed strand and one existing, light parent strand). These hybrids were then taken and placed in a new medium containing normal ammonium chloride (containing N-14). Now, it is known that E.coli replicates its genetic material every 20 minutes. After every single replication, it was found that only two types of DNA were formed :- hybrid and light (both are copies of pre-existing DNA strands), in equal proportion i.e. the ratio of light to hybrid DNA was 1:1. After every 20 minutes, the percentage of hybrid DNA reduced exponentially; by the fourth generation i.e. after 80 minutes of replication, the percentage of hybrid DNA was 12.5%.
These observations, and the lack of heavy DNA (both strands contain the heavy isotope of nitrogen), produced concrete proof that the parent DNA strands did not just clone themselves like cells. Rather, each strand was separated by some mechanism, and a new, complementary strand was synthesised, explaining the lack of heavy DNA in the experiment since the new medium, that was utilised in the growth of new DNA strands, lacked the isotope. This mechanism of replication was termed as a "semi-conservative model of replication", as it did not completely preserve the original DNA, yet the new DNA strands formed, depended on the original strands.
This mechanism, which we now know, involves the breakage of H- bonds by the use of enzymes called "helicases", followed by the relief of torsional strain as a result of the bonding between the nitrogenous bases, with an enzyme called "topoisomerase", which is vital in unwinding the DNA strands, formation of a 'fork', for ease of replication, and attachment of small RNA molecules called "primers", which would be used for the formation of the new DNA strands with the help of RNA-dependent DNA polymerase (specifically type III; there are three types), which utilises these primers as a starting point for strand formation. But here's the thing :- DNA replication, from an enzyme point of view, is not that straightforward. This is because the DNA polymerase is only programmed to form DNA strands from 5' to 3'-ends. The parent strand where such formation is feasible, is called the "leading strand". But this means that it would be very difficult to form a strand from 3' to 5'- end i.e. the complementary strand. But fret not, because there is a way out. The enzyme utilises the RNA primers to synthesise DNA strands, from 3' - 5' ends, in small fragments, called "Okazaki fragments", which are later joined together using DNA ligase enzymes, which do exactly what the name suggests :- join DNA fragments together. The strand where fragmented joining occurs, is called "lagging strand".
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