# Life’s First Molecule Was Protein, Not RNA

1. Nov 12, 2017

### Greg Bernhardt

https://www.quantamagazine.org/lifes-first-molecule-was-protein-not-rna-new-model-suggests-20171102/

2. Nov 12, 2017

### phyzguy

I find this stuff fascinating, but there is clearly no agreement yet. There is also this recent paper from Carter and WIlls, where they claim that both nucleic acid and proteins co-evolved together in the first life forms. They claim to have some experimental evidence that supports their hypothesis that I do not know enough about to evaluate the validity of their claim. So we have:

(1) RNA world - Nucleic acids came first - protein was added later. Many papers along these lines.
(2) The paper Greg cited - Protein came first, nucleic acid was added later.
(3) The paper I cited - The two co-evolved together. I like this paper in that they claim there were initially just two amino acids in the protein "alpahbet" (today there are 20), and more were added over time as complexity evolved.

3. Nov 13, 2017

### BillTre

I have some issues with this protein first approach compared with a previous thread (on the evolution of the ribosome and associated functions):

1) The model is not very detailed chemically (only 2 kinds of amino acids considered). Modern protein folding research/analysis/computer modelling is much more complex. Information is not being used (this chemical dumbing-down does not appeal to me).

2) Only an auto-catalytic sequences (of amino acids) would make more of themselves. Non-auto-catalytic sequences could catalyze the formation of other sequences, which could do other things, possibly even aid the catalytic sequence. Either way, producing an amino acid sequence based on the "reaction site" of a protein would seem to be limited to producing very specific sequences. it seems that the sequence at the reaction site would have to change to determine the reactions of a different sequence. Alternatively, the specificity of the sequences generated might be poor, which would allow a wider variety of sequences to be generated, but would also be less efficient. This would seem to be a big difficulty for this approach.

3) It is not clear to me that this underlies the origin of life (with other non-protein molecular stuff added later). Since the origin of life does not have an agreed upon definition, the line for a molecular system to cross to step into the world of the living is not defined. Instead, I see a more fruitful approach as looking for reasonable ways to assemble an interacting set of components that can:
• self-replicate (their own information laden sequences)
• create and maintain their own biochemical mini-environment (or local-environment), thus being able to control their replication and other processes
• dependably harness some source of energy (probably environment at first) to get things done
All of these steps are interesting.
After achieving them all, a majority might agree the system would be alive.

4) The ribosome evolution paper (comparatively, a very detailed analysis) talks about the both primitive proteins and RNAs being present as does the Carter and Wills article mentioned by @phyzguy. This seems more reasonable to me since there should be uncontrolled and undirected production of biochemicals prior to the precursors being swept up after biological processes evolve.
As the ribosome complex was assembled, proteins glommed onto its surface, adding stability and possible chemical functions.

5) The ribosome paper also mentioned that the proteins that are generated (by the proto-ribosome) would pass through a tunnel penetrating the ribosome which kepts the amino acid chains linear rather than allowing them to fold over and react with themselves (cyclizing) which could results in a population of amino acid loops 2 (or a few) amino acids long. These could not be further extended to longer chains (the amino and carboxyl sites of all amino acids all being used). This would limit the average complexity to the amino acid chains generated. Assuming the chemistry of this is correct, this would seem to argue against a proteins only approach.

4. Dec 12, 2017

### Leonardo Kelava

If something had to be first, I would always choose RNA.
Particularly considering the experiments of in vitro evolution of RNA in Szostak laboratories.

But, nonetheless, I think that the most plausible explanation is that two self-replicating molecules, RNAs and some simple crystal-like amino-acid sequences, combined together.

And personally, I am not sure that the first self-replicatin RNA-protein complex had to resemble ribosomes.
When comparing similarities of ribosomes between domains, that probably is the most likely

i would somehow give my advantage to signalling proteins, such are adenylyl cyclases or G-proteins.

5. Dec 12, 2017

### Dr. Courtney

I tend to be skeptical of unvalidated computations.

6. Dec 12, 2017

### rootone

Protein molecules can build physical structures. so they must have been first, RNA cannot do that.
RNA can change proteins though.
Chicken or egg?

7. Dec 12, 2017

### BillTre

RNA can built "physical structures" (meaning I guess not primarily for information conveyance):
ribosomes (mostly RNA)
ribozymes (act like enzymes)

As carriers of information, of course, they also have some physical structure to themselves.

8. Apr 6, 2018

### puppypower

One critical variable that is rarely included in the analysis of the formation of life, is water. If we took a cell and removed all the water, nothing works properly. If we replace the water with any other solvent, little if anything works and life is not evident. Water is critical to the shape and function of all bio-molecules. Life on earth evolved in water, which men's water set the micro-environment, for natural selection during abiogenesis.

The analogy would be animals evolving in the Arctic Region. This cold environment sets very specific constraints, in terms of what can work and want will not work. We can infer the preferred path of life from this environment. Water has unique properties and these properties places specific limits on the development of simple chemicals into life. The organic centric view of evolution is flawed, since it fails to take into account the nanoscale environmental potentials set by an aqueous environment. The result is sort of like guessing evolution, while leaving out the environmental factors, which help shape life.

For example, if we placed oil in water, these will not mix, but will form two layers. If blended our beaker of oil and water, these will form an emulation, as we add energy. If we wait, the emulsion will lower entropy away from this near solution, and form order, until only two layers remain. Water can push organic things into lowering entropy shapes. This is due to the free energy within the water. Free energy; G, is the sum of enthalpy and entropy; G= H-TS. In this case, enthalpy; H dominates entropy;S, A loss of entropy is possible, since the free energy still net decreases. Water's free energy, allow order to form within the organics. Protein folding is repeatable; probability of 1.0, since the final shape minimizes the free energy in the water. There is one minimum state.

If we mix water and oil, the two will separate. This lowers the free energy of water. Although this lowers the free energy of water, the entropy of the oil is still under the constraints of the second law, which states that this entropy still has to increase, but in other ways. One way to satisfy both water's free energy needs, and the second law for the oil, is to add hydrophilic groups to the oil. This increases water solubility for better entropy and its also minimizes the free energy of the water, even more. This is expected.

Abiogenesis needs a good theoretical water man to show how water sets the agenda, since it is the main environment at the nanoscale. In fact, a solid argument can be made the direction of evolution is connected to the free energy of water. it is not coincidental that the DNA is the most hydrated material in the cell; lowest free energy in water. This was always a goal from day one. If we use a water potential analysis, since RNA and DNA have the lowest free energy in water, these should have come later than protein.

Last edited: Apr 6, 2018
9. Apr 6, 2018

### Staff: Mentor

@puppypower - could you provide a reasonable citation for some of your claims? PF is a teaching environment, not a place for discussing new ideas. We work on proven Science only. Why? Because intelligent people love to "come up" with interesting ideas/hypotheses. Unfortunately most of these ideas have already been tested and discarded, so in a sense we are filtering out rejected hypotheses.

This triggered my response:
I am unaware of this in the standard literature, so if it exists, great! Otherwise, not acceptable ...and we will close the thread.

Thanks for understanding.

10. Apr 6, 2018

### puppypower

Water science is the most research area of science, in all of science. There more papers published about water that any other substance. Water has been researched since modern science began, and is still is being researched to answer new unanswered questions. The ideas presented are fundamental in terms of what is known about water.

The problem is not about acceptable science, as it is about the pitfalls of specialization within science. Specialization makes it hard for one hand of science to know what the other is doing. The biologist is organic centric, since water is a considered a solvent and appears boring compared, to the endless complex shapes and reactions of organic materials.

However, if we remove the boring water, nothing is the same right down to each enzyme. Run that dehydration experiment to verify this to yourself. Nothing works with the water gone. Simple inference should suffice. If we add water to say dehydrated yeast, life returns. The organics alone are not sufficient for life.

I am not a biologist so my knowledge of biology is only slightly above layman, in terns of details. But I am a water expert and a good bio-physical organic chemist. I am building a bridge between two areas of speciality science, both of which are nearsighted, that should be connected. They remain discontinuous due to the language and data barriers of specialization. I am building from the water side. For example below:

Nucleic acid hydration is crucially important for their conformation and utility [1093828542bÅ 11 bp, B-DNA pitch 34 Å 10 bp, C-DNA pitch 31Å 9.33 bp, D-DNA pitch 24.2 Å 8 bp and the left-handed Z-DNA pitch 43Å 12 bp) with differing hydration. The predominant natural DNA, B-DNA, has a wide and deep major groove and a narrow and deep minor groove and requires the greatest hydration. Lowering the hydration (for example by adding ethanol) may cause transitions from B-DNA to A-DNA [2784] to Z-DNA.

The various conformations of the DNA; B,C,D,Z differ by the amount of hydration. The organic aspect of the DNA is fixed in all four conformations and does not explain these differences. The water determines which conformation, as well as many other things fro signally to binding energetics. It is not coincidence the most common conformation of the DNA, is also the most hydrated. A water-centric person can create a fresh look at an old problem, since water is the nanoscale environment for abiogenesis.

Last edited: Apr 6, 2018
11. Apr 6, 2018

### Ygggdrasil

As a water expert and bio-physical organic chemist, you should review your physical chemistry. The separation of water and oil, known as the hydrophobic effect, is in fact driven by an increase in entropy. Solvating non-polar oil molecules in water requires water to adopt a more ordered structure. In order to minimize the amount of ordered water molecules, the system will minimize the amount of surface area that needs to be solvated, which results in the aggregation of oil into large droplets that are separated from the water. For a more detailed explanation, see: https://pubs.acs.org/doi/abs/10.1021/ed075p116

You are also making some strange claims about the "organic centric" view of abiogenesis. Of course, all biologists and chemists researching the issue know about the importance of water. It is well known that water is an important factor in maintaining the structures of nucleic acids and proteins. All experiments related to abiogenesis take into account that these early reactions were taking place in an aqueous environment. A major Nobel-prize winning researcher in this area has focused his research on understanding how phenomena like the hydrophobic effect drive assembly of biomolecules into protocells in aqueous environment.

12. Apr 6, 2018

### puppypower

I sorry if I am diverting the discussion. However, this detour background will help address the topic.

The term hydrophobic is a misnomer. Organics are not afraid of water, since water can form low energy hydrogen bonds with any organic. These weaker hydrogen bonds are not much different in energy than organic-organic interactions. The oil is fine with this. It is not afraid of the water. The real drive in the hydrophobic affect is water wanting to segregate. Water can do much better, energy wise, if water can form all its hydrogens bonds with just water.

The unusually high boiling point of water, relative to its small mass; 18 grams/mole, is implicit of the internal binding strength of the aqueous hydrogen bonding environment. The boiling point of molecules with the same weight as water are as follows; H2O, is 100C, NH3 is -33C, and CH4 is -258C. Water is able to form 4 hydrogen bonds, with other water, which is loosely analogous to carbon; extended secondary water structuring.

Ammonia can form hydrogen bonds, but the imbalance between donors; 3 and receivers; 1 make NH3 less internally bound; easy to evaporate. Ammonia is a good degreaser, even though polar, since its global matrix is weaker than water, and hydrogen bonding to grease and oil does not have the same global energy cost as it does for water.

Hydrogen bonds between water and oil are much weaker that water-water, and will cause residual free energy to remain in the affected water. The water, as a whole, will attempt to maximize its internal hydrogen bonding, and minimize its free energy. This can be done by segregating the oil. Ammonia will not push out the oil, since this will lower the system entropy.

If we start with a beaker of oil in water and agitated the beaker, the incorporation of the oil into the water matrix, to form an emulsion, disrupts the global integration of the water; adds points of disorder to the interaction of the bulk state. The oil creates breaks in the 4 hydrogen bonding continuum; higher free energy points and expanded distances; higher global aqueous entropy. In other words, water goes from 4 to 3 hydrogen bonds to other water; donors and accepters are no longer in balance so the matrix suffers.

The analogy is a group of biologist; water, are discussing evolution and abiogenesis. Since they are all the same specialty, and all have the same training and use the same words and theories, this allows for smooth interaction as a group. This is a glass of water. If we were to add a theoretical chemist, to the discussion, drop of oil, the oil is fine with this arrangement, since evolution is biology, and you can learn something. However, the oil may not be as welcome, since he is not with the program. This can cause entropy to increase; stress. If they can segregate the chemist, order can be restored; lower the system entropy.

What you said was true of an isolated caging of an organic molecule. But a small volume of water is not easy to isolate from the bulk. When you deal with a cell, you need to look at water as one large connected thing, that touches everything. This is how water helps the cell integrate. Various organics surfaces impact the water differently. The potential in the water matrix can be in the form of gradients. The water tries to balance this; diffusion and reactions.

13. Apr 6, 2018

### TeethWhitener

You missed the point of @Ygggdrasil 's post. The free energy of mixing water and oil is positive. The enthalpy of mixing is negative (the internal energy is also negative, if you want to use Helmholtz free energy instead of Gibbs). Thus, since $\Delta G = \Delta H - T\Delta S$, and $\Delta H < 0, \Delta G > 0$, it must be the case that $\Delta S < 0$. This also implies that mixing becomes more favorable at lower temperatures (hydrophobes are more soluble at lower temperatures), which is exactly what is observed. This (possibly paywalled) article by Widom et al. explains it in detail:
http://pubs.rsc.org/en/content/articlelanding/2003/cp/b304038k/unauth#!divAbstract

14. Apr 6, 2018