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DNA is just one of millions of possible genetic molecules



November 11, 2019

(Nanowerk News) Biology encodes information into DNA and RNA, which are complex molecules finely tuned to their functions. But are they the only way to store hereditary molecular information? Some scientists believe that life, as we know it, could not have existed before nucleic acids existed, so understanding how they existed on primitive Earth is a primary goal of basic research.

The central role of nucleic acids in the flow of biological information also makes them key targets for pharmaceutical research, and synthetic nucleic acid-mimicking molecules form the basis of many treatments for viral diseases, including HIV. Other polymers similar to nucleic acid are known, but it remains unknown as to possible alternatives for heritable data storage.

Using sophisticated computational methods, scientists from the Institute for Earth-Life Science (ELSI) at the Tokyo Institute of Technology, the German Aviation Center (DLR) and Emory University investigated the "chemical neighborhood" of nucleic acid analogues.

Surprisingly, they found just over a million variants, suggesting a vast unexplored universe of chemistry relevant to pharmacology, biochemistry, and efforts to understand the origin of life. The molecules detected by this study (Journal of Chemical Information and Modeling, “One among millions: the chemical space of nucleic acid-like molecules”) could be further modified to yield hundreds of millions of potential pharmaceutical potential drugs.

Nucleic acids were first identified in the 19th century, but their composition, biological role and function were not understood by scientists until the 20th century. The discovery of the double stranded DNA structure of Watson and Crick in 1953 revealed a simple explanation of how biology and evolution work.

All living things on Earth store information in DNA, which consists of two polymer wires wrapped around each other like a caduceus, each strand being an addition to the other. When the strands are separated, copying a complement to any template results in two copies of the original.

The DNA polymer itself is made up of a series of "letters", bases of adenine (A), guanine (G), cytosine (C) and thymine (T), and living organisms have evolved to ensure that they are almost always safe during DNA copying. the corresponding string of letters is played. The sequence of bases is mapped into RNA proteins and then read into the protein sequence. The proteins themselves then provide a wonderland of fine-tuned, life-sustaining chemical processes.

Small errors occasionally occur during DNA copying and others are sometimes introduced by environmental mutagens. These small bugs are food for natural selection: some of these bugs result in sequences that produce well-functioning organisms, though most have poor effects and are considered even deadly by many.

The ability of new arrays to enable their hosts to survive better is a "ratchet" that allows biology to almost magically adapt to the continuing challenges that the environment provides. This is the root cause of the kaleidoscope of biological forms we see around us, from humble bacteria to tigers, the information stored in nucleic acids makes it "memorable" in biology.

But are DNA and RNA the only way to store this information? Or maybe they are just the best way, discovered only after millions of years of evolutionary wandering?

"There are two types of nucleic acids in biology and maybe 20 or 30 effective nucleic acid-binding analogues. We wanted to know if there was another or even a million more. The answer seems to be much, much more than expected." , says Professor Jim Cleaves of ELSI.

Although biologists do not consider them organisms, viruses also use nucleic acids to store their inherited information, though some viruses use a small variant on DNA, RNA, as their molecular storage system. RNA differs from DNA in the presence of one atom substitution, but total RNA plays by very similar molecular rules to DNA.

The remarkable thing is that, among the incredible diversity of organisms on Earth, these two molecules are basically the only ones that biology uses.

Biologists and chemists have long wondered why this should be. Are these the only molecules that could perform this function? If not, are they perhaps the best, that is, other molecules could play this role, and maybe biology tried them out during evolution?

The central importance of nucleic acids in biology has also long made them drug targets for chemists. If a drug can inhibit the ability of an organism or virus to pass on its knowledge of infectiousness to posterity, it effectively kills the organisms or virus. Hiding the inheritance of an organism or virus is a great way to destroy it.

Fortunately for chemists and all of us, the cellular machines that control the copy of nucleic acids in each organism are slightly different, and often very different in viruses.

Organisms with large genes, such as humans, should be very careful when copying their ancestral data and therefore be very selective when not using the wrong precursors when copying their nucleic acids. In contrast, viruses, which generally have much fewer genomes, are much more tolerant of using similar but slightly different copy molecules.

This means that chemicals similar to nucleic acid building blocks, known as nucleotides, can sometimes disrupt the biochemistry of one organism worse than another. Most important antiviral drugs used today are nucleotide (or molecule-differentiated by phosphate group) analogues, including those used to treat HIV, herpes, and viral hepatitis.

Many important cancer drugs are also nucleotide or nucleoside analogues, because cancer cells sometimes have mutations that make them copy nucleic acids in an unusual way.

"Trying to understand the nature of inheritance and how it might be embodied is about the most basic research that can be done, but it also has some really important practical applications," says co-author Chris Butch, formerly ELSI and now professor at Nanjing University.

Because most scientists believe that the basis of biology is inherited information, without which natural selection would be impossible, evolutionary scientists studying the origin of life have also focused on ways to make DNA or RNA from simple chemicals that could spontaneously appear on primitive Earth. If nucleic acids existed, many problems in the origin of life and early evolution would make sense.

Most scientists believe that RNA evolved before DNA, and for the subtle chemical reasons that make DNA much more stable than RNA, DNA has become the hard drive of life. However, research in the 1960s soon split the field of theoretical origin into two: those who saw RNA as a simple "Occam's razor" response to the problem of the origin of biology and those who saw many kinms in the armor of abiological RNA synthesis. RNA is still a complicated molecule, and it is possible that structurally simpler molecules could have served in its place before they were formed.

Co-author Dr. Jay Goodwin, a chemist at Emory University, says it's "really exciting to consider the potential of alternative genetic systems based on these analogous nucleosides – that they may have evolved and evolved in different environments, maybe even in other planets or moons in our solar system. These alternative genetic systems could extend our conception of the central dogma of biology into new evolutionary directions, in response and robust to increasingly challenging environments here on Earth.

To examine all these basic questions, which molecule was the first, which is unique about RNA and DNA, all at once physically making molecules in the laboratory, is difficult. On the other hand, calculating molecules before being made could potentially save doctors a lot of time.

"We are surprised at the result of this calculation," says co-author Dr. Markus Meringer, "it would be very difficult to estimate in advance that there are more than a million nucleic acids like scaffolds. Now we know, and we can start examining some of these in the lab."

"It's absolutely fascinating to think that using modern computing techniques we can come up with new drugs when looking for alternative DNA and RNA molecules that can store inherited information. Cross-disciplinary studies like this make science still challenging and fun." Pieter Burger, also from Emory University.


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