DNA is only one among millions of possible genetic molecules

Scientists computed a zoo of millions of alternate genetic polymer molecular structures, giving context for why biology encodes information how it does, and providing potential leads for new drugs and a guide to searches for extraterrestrial biology.

Biology encodes hereditary data in DNA and RNA, which are finely tuned to their biological functions and modes of biological production. The vital role of nucleic acids in biological information flow makes them key targets of pharmaceutical research.

But, are they the only way to store hereditary molecular information?

Other nucleic acids like polymers are known, yet much remains obscure with respect to potential alternatives for hereditary information storage.

For the first time, scientists at the Earth-Life Science Institute (ELSI) at the Tokyo Institute of Technology, the German Aerospace Center (DLR) and Emory University- used sophisticated computational methods to investigate the “chemical neighborhood” of nucleic acid analogs.

Notably, they found well over a million variants. This opens up about a vast unexplored chemistry world relevant to pharmacology, biochemistry, and efforts to understand the origins of life.

Professor Jim Cleaves of ELSI said, “There are two kinds of nucleic acids in biology, and maybe 20 or 30 effective nucleic acid-binding nucleic acid analogs. We wanted to know if there is one more to be found or even a million more. The answer is, there seem to be many, many more than was expected.”

Although scientists don’t consider them organisms, viruses also use nucleic acids to store their heritable information. However, some infections use a slight variation on DNA, RNA, as their molecular storage system. RNA varies from DNA in the presence of a single atom substitution, yet overall RNA plays by very similar molecular rules as DNA. The remarkable thing is, among the incredible variety of organisms on Earth, these two molecules are the main ones biology uses.

Scientists have long wondered, are these the only molecules that could perform this function? If not, are they perhaps the best, that is to say, other molecules could play this role, and perhaps biology tried them out during evolution?

The central importance of nucleic acids in biology has also long made them drug targets. If a drug can inhibit the ability of an organism or virus to pass its knowledge of how to be irresistible on to offspring, it adequately kills the organisms or viruses. Mucking up the heredity of an organism or virus is a great way to knock it dead. Fortunately for chemists, and all of us, the cell machinery which oversees nucleic acid duplicating in each organism is slightly different, and viruses often very different.

Organisms with large genomes, like humans, need to be very careful about copying their hereditary information and thus are very selective about not using the wrong precursors when copying their nucleic acids. Conversely, viruses, which generally have much smaller genomes, are much more tolerant of using similar, but slightly different molecules to copy themselves.

This means chemicals that are similar to the building blocks of nucleic acids, known as nucleotides, can sometimes impair the biochemistry of one organism worse than another. Most of the important anti-viral drugs used today are nucleotide (or nucleoside, which are molecule differing by the removal of a phosphate group) analogs, including those used to treat HIV, herpes, and viral hepatitis. Many important cancer drugs are also nucleotide or nucleoside analogs, as cancer cells sometimes have mutations that make them copy nucleic acids in unusual ways.

Co-author Chris Butch, formerly of ELSI and now a professor at Nanjing University, said, “Trying to understand the nature of heredity, and how else it might be embodied, is just about the most basic research one can do, but it also has some critical practical applications.”

Co-author Dr. Jay Goodwin, a chemist with Emory University, says, “It is truly exciting to consider the potential for alternative genetic systems, based on these analogous nucleosides – that these might have emerged and evolved in different environments, perhaps even on other planets or moons within our solar system. These other genetic systems might expand our conception of biology’s ‘central dogma’ into new evolutionary directions, in response and robust to increasingly challenging environments here on Earth.”

Co-author Dr. Markus Meringer said, “Examining all of these basic questions, which molecule came first, what is unique about RNA and DNA, all at once by physically making molecules in the laboratory, is difficult. On the other hand, computing molecules before making them could potentially save chemists a lot of time. We were surprised by the outcome of this computation. It would be complicated to estimate a priori that there are more than a million nucleic-acid like scaffolds. Now we know, and we can start looking into testing some of these in the lab.”

Co-author Dr. Pieter Burger, also of Emory University, said, “It is fascinating to think that by using modern computational techniques we might stumble upon new drugs when searching for alternative molecules to DNA and RNA that can store genetic information. It is cross-disciplinary studies such as this that make science challenging and fun yet impactful.”

The study is published in the Journal of Chemical Information and Modeling.

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