Lipid-Driven Biophysical Selection of β-Furanoside-5'-Phosphate as the Sole Scaffold of Extant RNA
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eLife Assessment
The study reports on the relative lipid permeabilities of different ribonucleotide isomers. The findings are valuable for prebiotic chemistry and protocell research because they offer an additional possible explanation for how the canonical ribonucleotide isomers were selected. The strength of the evidence is solid, being supported by experimental and computational approaches, although the step from differential permeability to selection is less firmly supported.
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Abstract
The emergence of RNA's primordial backbone presents a fundamental question in the study of life's origins: why was β-furanoside-5'-phosphate selected over other isomeric alternatives as the predominant building block during the origin of life? In contrast to previous studies that have demonstrated selective synthetic routes to canonical RNA structures, we explore biophysical factors that selectively favor β-furanoside and 5'-nucleotide over their undesired isomers. Inspired by the chromatographic elution order of nucleoside and nucleotide isomers, we establish a new selection model to discriminate between them. β-Furanoside is found to be more lipid-permeable than any other configurational isomer, making it the most abundant species after permeation. Outward permeation selectively screens intracellularly formed nucleotides, enriching 5'-nucleotide as the primary RNA building block within a protocell. The unique properties of representative canonical nucleosides and nucleotides are rationalized based on both their structural and dynamic characteristics, as elucidated by DFT and MD calculations. A scenario in which β-furanoside selectively accumulates in a lipid droplet is further investigated using a specifically designed micromixer. Together, these findings suggest the existence of a primitive selection mechanism driven by purely biophysical forces, which may have played a critical role in advancing key steps in the progression of primitive biomolecules.
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eLife Assessment
The study reports on the relative lipid permeabilities of different ribonucleotide isomers. The findings are valuable for prebiotic chemistry and protocell research because they offer an additional possible explanation for how the canonical ribonucleotide isomers were selected. The strength of the evidence is solid, being supported by experimental and computational approaches, although the step from differential permeability to selection is less firmly supported.
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Reviewer #1 (Public review):
Summary:
The authors have carried out a study of lipid membrane permeabilities on different nucleoside/tide isomers. The study primarily relied on PAMPA as the experimental technique for assessing permeabilities, although interestingly, the authors found that there was a correlation between permeability and retention time on a C18 column. The authors specifically looked at the permeabilities of furano and pyrano alpha/beta nucleosides/tides, since a major question is why biochemistry uses only the beta furano isomers, when three other isomers based on anomeric configuration and ring size are also possible. The authors found that for all A, U, G or C nucleoside isomers, the beta-furanoside is consistently the most lipid-permeable. These findings were also supported by computational (DFT and MD) studies. The …
Reviewer #1 (Public review):
Summary:
The authors have carried out a study of lipid membrane permeabilities on different nucleoside/tide isomers. The study primarily relied on PAMPA as the experimental technique for assessing permeabilities, although interestingly, the authors found that there was a correlation between permeability and retention time on a C18 column. The authors specifically looked at the permeabilities of furano and pyrano alpha/beta nucleosides/tides, since a major question is why biochemistry uses only the beta furano isomers, when three other isomers based on anomeric configuration and ring size are also possible. The authors found that for all A, U, G or C nucleoside isomers, the beta-furanoside is consistently the most lipid-permeable. These findings were also supported by computational (DFT and MD) studies. The authors conclude that such a property could plausibly have been a chemical selection mechanism that favoured these isomers when they first started interacting with protocell membranes.
Strengths:
There are two major strengths to this study: (1) it offers an alternative/additional explanation backed by experimental and computational evidence as to how the canonical ribonucleotides (namely, the beta-furanoside isomers) were selected by interactions with protocell membranes; (2) it makes the important observation that retention time on a C18 column is correlated with permeabilities determined by PAMPA, the "industry standard", suggesting that LC could also be a convenient way to assess relative permeabilities of analytes of interest. With this report, there are many promising follow-up studies that can be carried out in the context of synthetic lipid protocells in order to further support the hypothesis that selective permeability played a major role in early chemical/Darwinian evolution.
Weaknesses:
The biggest weakness is that there needs to be more of a critical discussion of chemical vs Darwinian selection. There are two basic hypotheses for how the canonical ribonucleotides came to be: they were the products of prebiotic synthesis and chemical selection pressures, or they emerged as a product of natural selection after Darwinian evolution already became established. While the experimental evidence in terms of ribonucleotide prebiotic synthesis is discussed well, the work of Eschenmoser in particular, which supports the alternative hypothesis that RNA is the product of Darwinian evolution, should be discussed in more detail on page 4.
The authors should also acknowledge somewhere in the discussion/conclusion that there is a certain amount of bias that the field has towards extant biology, and this bias could be influencing how certain results are interpreted as beneficial for ribonucleotide selection, when the same result might be used to argue against it. For example, the fact that the 2',3'-cyclic phosphates are the most permeable among the phosphate regioisomers might be used to argue these were the preferred substrates for oligomerization in a protocell, given it had a catalyst which could do it, like a short peptide. While the differences in permeabilities are quite solid, what it means in terms of selection could be applied to multiple, specific scenarios, each with its own interpretations and implications.
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Reviewer #2 (Public review):
Summary:
The authors ask whether membrane transport could have contributed to the emergence of the molecular configuration characteristic of extant RNA. They examine the permeability of α- and β-furanosides and of different nucleotide phosphate isomers using fatty-acid-based PAMPA systems, supported by partitioning experiments and molecular simulations.
The central finding is that closely related molecular species show different transport behaviour: β-furanosides are preferentially transported, while 5′-phosphorylated nucleotides are less permeable than 2′- and 3′-phosphates. These observations are potentially interesting because membrane transport could influence the composition of an evolving compartment.Strengths:
(1) The study addresses an interesting and relatively underexplored role for membranes in …
Reviewer #2 (Public review):
Summary:
The authors ask whether membrane transport could have contributed to the emergence of the molecular configuration characteristic of extant RNA. They examine the permeability of α- and β-furanosides and of different nucleotide phosphate isomers using fatty-acid-based PAMPA systems, supported by partitioning experiments and molecular simulations.
The central finding is that closely related molecular species show different transport behaviour: β-furanosides are preferentially transported, while 5′-phosphorylated nucleotides are less permeable than 2′- and 3′-phosphates. These observations are potentially interesting because membrane transport could influence the composition of an evolving compartment.Strengths:
(1) The study addresses an interesting and relatively underexplored role for membranes in prebiotic chemical evolution.
(2) The comparison of closely related molecular species provides a potentially useful demonstration that membrane transport can discriminate between different nucleotide configurations. The experimental and computational approaches complement each other.
(3) The analysis of 5′-, 2′-, 3′- and cyclic phosphate species is particularly interesting and could provide a useful framework for thinking about how membrane transport interacts with nucleotide chemistry.
Weaknesses:
(1) The principal concern is that the manuscript moves from differential permeability to evolutionary selection rather too quickly. The experiments demonstrate differences in transport, but do not establish that these differences would produce sufficient intracellular enrichment, persistence or functional consequences to drive selection of the canonical RNA configuration.
(2) The relevance of the PAMPA system to primitive vesicles is also not fully established. Membrane permeability depends strongly on membrane composition and environmental conditions, and the relationship between the membrane compositions used in the principal experiments and plausible primitive vesicles needs to be clearer.
(3) Similarly, the pH-gradient experiments show an effect of pH on transport, but a gradient between two macroscopic PAMPA reservoirs does not demonstrate that primitive fatty-acid vesicles could maintain a comparable gradient.
(4) Finally, some of the key results are presented as changes in relative composition rather than direct measurements of molecular flux. The distinction between compositional enrichment, partitioning and permeability should therefore be clearer. The molecular simulations provide useful support but, given the small calculated free-energy differences and acknowledged limitations in the nucleotide simulations, do not independently establish the mechanism.
Overall, the work contains potentially valuable observations, but I think the conclusions should be framed more cautiously. The most compelling interpretation is that membrane transport could have been one component of a multifactorial chemical-selection process, alongside prebiotic synthesis, stability and nucleotide chemistry, rather than that membrane permeability itself explains the emergence of canonical RNA.
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