In this paper K\u00c3\u00b6nny? and colleagues extend their Metabolically Coupled Replicator
\n System (MCRS) to simulate the early evolution of metabolically coupled ribozymes on
\n a mineral surface. The main novelty in their approach is the explicit calculation
\n of RNA secondary structures and minimal free energies for the evolving sequences and
\n the use of the calculated parameters for the model simulations. This makes the model
\n more realistic than the earlier versions. I suggest that the authors state more explicitly
\n what are the new insights gained from using the more realistic secondary structure
\n and free energy calculations. For example the authors observe that: \u00e2\u20ac\u0153The shorter (faster
\n replicable) mutants of the parasitic mutants are heavily selected against due to the
\n disadvantage of aggressive parasites\u00e2\u20ac\u009d. Was this already shown in the less explicit
\n versions of the MCRS model? An extra paragraph in the Conclusions section could summarize
\n the novel results.\n <\/p>\n
Two extra paragraphs have been added to Conclusions section summarizing the novelties It would be interesting to see results with larger metabolic neighbourhood (h?=?7\u00c3\u20147) The results of the simulations with h?=?7\u00c3\u20147 and D?=?4 (Figure<\/em>3 ) show that increasing metabolic neighbourhood size, even if it decreases replicator Importantly, the authors should provide their code as an Additional file or deposit As the code is the result of a long process of development, and it will be further Minor comments:<\/p>\n pg 19\u00e2\u20ac\u201c20 The discussion about the dynamics of parasites is repetitive in this section. We have shortened this part.<\/em><\/p>\n Typos:<\/p>\n page 11: \u00e2\u20ac\u0153we assume that different RNS molecules\u00e2\u20ac\u009d change to RNA<\/p>\n Corrected.<\/em><\/p>\n page 17: \u00e2\u20ac\u0153i.e., larger metabolic neighbourhood) that fosters parasite invasion, which Corrected.<\/em><\/p>\n This is a very elegant study which has been explained in very accessible language. We thank the Reviewer for their positive judgment of the study.<\/em><\/p>\n For my money, the most exciting result is that this model suggests that catalytic Lehman and co-workers showed that mixtures of RNA fragments that self-assemble into Just a minor quibble about this statement in the Background: \u00e2\u20ac\u0153recent organisms still Thanks for drawing our attention to the paper \u00e2\u20ac\u201c we have cited it in the corresponding Minor comments\/typos (can be deleted from the review once addressed):<\/p>\n Page 7, the use of the term \u00e2\u20ac\u0153catching\u00e2\u20ac\u009d \u00e2\u20ac\u201c perhaps \u00e2\u20ac\u0153binding\u00e2\u20ac\u009d is more appropriate here. We rephrased the sentence in a more clear way.<\/em><\/p>\n Page 11, \u00e2\u20ac\u0153hydroxil\u00e2\u20ac\u009d should be hydroxyl<\/p>\n Corrected.<\/em><\/p>\n P11, RNS should be RNA<\/p>\n Corrected.<\/em><\/p>\n P26, \u00e2\u20ac\u0153thedesing\u00e2\u20ac\u009d should be the design<\/p>\n Corrected.<\/em><\/p>\n Figure\u00c2\u00a02 X-axes: Ferquency\n <\/p>\n Corrected.<\/em><\/p>\n K\u00c3\u00b6nny? and co-workers have attempted to fill the gap between purely mathematical, Major comment:<\/p>\n 1) My major concern is the plausibility of the metabolic part of the model. The authors We absolutely agree with the Reviewer in that even a very simple realistic metabolism Minor comments:<\/p>\n 2) The manuscript would benefit from a graphical presentation of the focal cell with We added a figure that explains metabolic and replicator neighbourhood configurations.<\/em><\/p>\n 3) It is not clear how the model accounts for \u00e2\u20ac\u0153the time consumption of \u00e2\u20ac\u0153releasing\u00e2\u20ac\u009d We rephreased it in a more clear way.<\/em><\/p>\n 4) The statement that \u00e2\u20ac\u0153replication is possible only in the unfolded state\u00e2\u20ac\u009d should Indeed, we cannot exclude the possibility of the simultaneous unfolding and replication References<\/p>\n [1] A.I. Oparin, The Origin of Life, Moskowskiy rabochiy, Moscow, 1924.<\/p>\n [2] J.B.S. Haldane, The Origin of Life, in: C.A. Watts (Ed.) The Rationalist Annual [3] N.H. Horowitz, On the Evolution of Biochemical Syntheses, Proc. Natl. Acad. Sci. [4] S.L. Miller, L.E. Orgel, The Origins of Life, Prentice Hall Englewood Cliffs, [5] A. Lazcano, S.L. Miller, On the origin of metabolic pathways, J. Mol. Evol., 49 [6] S.A. Benner, H.J. Kim, M.A. Carrigan, Asphalt, water, and the prebiotic synthesis [7] R. Saladino, C. Crestini, S. Pino, G. Costanzo, E. Di Mauro, Formamide and the [8] A.Y. Mulkidjanian, A.Y. Bychkov, D.V. Dibrova, M.Y. Galperin, E.V. Koonin, Origin [9] D.V. Dibrova, M.Y. Chudetsky, M.Y. Galperin, E.V. Koonin, A.Y. Mulkidjanian, The [10] M.W. Powner, B. Gerland, J.D. Sutherland, Synthesis of activated pyrimidine ribonucleotides [11] M.W. Powner, J.D. Sutherland, J.W. Szostak, Chemoselective multicomponent one-pot [12] A.Y. Mulkidjanian, D.A. Cherepanov, M.Y. Galperin, Survival of the fittest before Reviewer 1: G\u00c3\u00a1sp\u00c3\u00a1r J\u00c3\u00a9kely In this paper K\u00c3\u00b6nny? and colleagues extend their Metabolically Coupled Replicator System (MCRS) to simulate the early evolution of metabolically coupled ribozymes on a mineral surface. The main novelty in their approach is the explicit calculation of RNA secondary structures and minimal free energies for the evolving sequences and the use […]<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[],"tags":[],"class_list":["post-13608","post","type-post","status-publish","format-standard","hentry"],"_links":{"self":[{"href":"http:\/\/healthmedicinet.com\/news\/wp-json\/wp\/v2\/posts\/13608","targetHints":{"allow":["GET"]}}],"collection":[{"href":"http:\/\/healthmedicinet.com\/news\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"http:\/\/healthmedicinet.com\/news\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"http:\/\/healthmedicinet.com\/news\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"http:\/\/healthmedicinet.com\/news\/wp-json\/wp\/v2\/comments?post=13608"}],"version-history":[{"count":0,"href":"http:\/\/healthmedicinet.com\/news\/wp-json\/wp\/v2\/posts\/13608\/revisions"}],"wp:attachment":[{"href":"http:\/\/healthmedicinet.com\/news\/wp-json\/wp\/v2\/media?parent=13608"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"http:\/\/healthmedicinet.com\/news\/wp-json\/wp\/v2\/categories?post=13608"},{"taxonomy":"post_tag","embeddable":true,"href":"http:\/\/healthmedicinet.com\/news\/wp-json\/wp\/v2\/tags?post=13608"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}
\n of the results.<\/em><\/p>\n
\n and higher replicator diffusion. One would expect that parasitic sequences can diverge
\n more since they will not as easily demolish metabolism in their own vicinities, due
\n to larger diffusivity.\n <\/p>\n
\n frequency, does not affect the stable persistence of the system. Its stationary characteristics
\n (the equilibrium distributions of replicator frequencies, enzymatic activities and
\n sequence chain lengths) have also been largely insensitive to the actual value of
\n the dispersal parameter D (Figure<\/em>4 ). This is in good accordance with our previous results [19] obtained with toy model
\n simulations scanning a wide range of the (D, h, r) parameter space. The earlier study
\n revealed a positive effect of increasing dispersal (D) which prevents the aggregation
\n of conspecific replicators, and a negative effect of increasing h, though approximating
\n the mean-field situation that is known to go extinct. The deleterious effect of larger
\n h can be compensated by increasing D to some extent, but the compensatory effect is
\n limited: at too large metabolic neighbourhood sizes the system collapses anyway (cf.
\n [19]: Figures<\/em>2 and<\/em>4 ). The parameter setting suggested by the Reviewer (large h, large D) is, unfortunately,
\n practically not feasible in the explicit model, because even on a high-capacity grid
\n computer it would take months to run a single simulation. The huge difference between
\n the CPU time demands of the toy models and the present one is due to the \u00e2\u20ac\u0153handling
\n time\u00e2\u20ac\u009d of sequence folding. However, the results of the toy models are likely to carry
\n over to the explicit case in this respect, too, since in all other respects we experienced
\n qualitative matches.<\/em><\/p>\n
\n it to a public repository for others to reproduce or extend the model calculations.\n <\/p>\n
\n developed for later studies, we do not find it convenient to publish it at this stage.
\n However, we are willing to send the code to the reviewer or to anyone for further
\n studies or for reproducing our results, on an individual basis.<\/em><\/p>\n
\n I suggest to delete or shorten this part: \u00e2\u20ac\u0153Mono-active replicators easily mutate to
\n parasitic ones \u00e2\u20ac\u00a6 their own vicinities and starve to death\u00e2\u20ac\u009d.\n <\/p>\n
\n is evident on Figure\u00c2\u00a04A\u00e2\u20ac\u009d. \u00e2\u20ac\u201c change to Figure\u00c2\u00a03A\n <\/p>\nReviewer 2: Anthony Poole<\/h4>\n
\n I found the results very insightful, and need say little other than that, for those
\n interested in the RNA world, this is a paper well worth reading.\n <\/p>\n
\n promiscuity in early ribozymes may have been extremely short-lived. This bears thinking
\n about, particularly given the view, popular in protein science circles that early
\n enzymes were promiscuous (both in their substrate specificity and enzymatic reactions).
\n It is also noteworthy that group selection appears as a feature of the model. This
\n is broadly consistent with the cooperative networks that Lehman and colleagues observed
\n for fragmented ribozymes (Nature 491:72\u00e2\u20ac\u201c77). I would be interested to see a brief
\n discussion of that work and how it relates to the authors\u00e2\u20ac\u2122 findings.\n <\/p>\n
\n self-replicating ribozymes can form catalytic cycles and more complex networks. We
\n agree that some aspects of our model show some similarity to some of Lehman\u00e2\u20ac\u2122s, even
\n though the two models (Lehman\u00e2\u20ac\u2122s and ours) are essentially different in their basic
\n assumptions. Ours assumes cooperation in the evolutionary sense, so that a complete
\n metabolic neighbourhood (a cooperating \u00e2\u20ac\u0153team\u00e2\u20ac\u009d of potentially competing replicators)
\n is capable of replicating a focal sequence which thus will have two identical copies
\n locally (apart from mutations). The model of Lehman, on the other hand, assumes collective
\n autocatalysis: in which the complex networks arise due to the fact that the members
\n of the set catalyze each other\u00e2\u20ac\u2122s formation, rather than replication. Yet, it is true
\n that both models are prone to being parasitized and ultimately exterminated by parasitic
\n replicators in a mean-field framework, both requiring some form of spatial structure
\n as a potential defense: \u00e2\u20ac\u0153Longer term evolutionary optimization would have required
\n spatial heterogenity or compartmentalization to provide lasting immunity against parasitic
\n species or short autocatalytic cycles.\u00e2\u20ac\u009d (Vaidya et al. Nature 491:77 (2012)).<\/em><\/p>\n
\n carry reliable clues suggesting that RNA had played a central role both in the metabolism
\n and in the genetics of very early forms of life [3,4]\u00e2\u20ac\u009d. The papers cited here are
\n both excellent, but address the more chemical aspects of the origin of RNA itself
\n and of RNA catalysis. By contrast, the recent paper by Hoeppner et al. (PLoS Comp
\n Biol 8: e1002752. http:\/\/dx.doi.org\/10.1371\/journal.pcbi.1002752) used a comparative genomic approach to look at whether there are \u00e2\u20ac\u02dcclues\u00e2\u20ac\u2122 of the
\n RNA world in modern organisms, so is perhaps more appropriate, given the sentence.\n <\/p>\n
\n part of the text.<\/em><\/p>\n
\n Enzymologists routinely talk about substrate binding and product release.\n <\/p>\nReviewer 3: Armen Mulkidjanian<\/h4>\n
\n \u00e2\u20ac\u0153toy\u00e2\u20ac\u009d modeling of very early evolution and the physico-chemical realm within which
\n such evolution may have proceeded. Specifically, the model of K\u00c3\u00b6nny? and co-workers
\n explicitly accounts for the primary and secondary structure of replicators. Hopefully,
\n the authors would continue their efforts to model the physics and chemistry of the
\n early evolution. Therefore, the comments below contain certain recommendations which
\n could be realized either upon revising of the given manuscript or in the future work
\n of the authors.\n <\/p>\n
\n assumed that \u00e2\u20ac\u0153the different RNA species cooperate to produce monomers for their own
\n replication, and possibly also to supply other \u00e2\u20ac\u0153common goods\u00e2\u20ac\u009d for the replicator community\u00e2\u20ac\u009d.
\n Thereby, only three catalytic activities were assumed to be sufficient to perform
\n all these functions in the model of the authors. Obviously, the assumption of only
\n three catalytic activities is an oversimplification, which is quite understandable
\n in the given context. In a wider context, however, the source of monomers and \u00e2\u20ac\u0153common
\n goods\u00e2\u20ac\u009d for the first replicators is one of the open questions in the origin of life
\n research. Apparently much more than three catalytic activities should have been simultaneously
\n needed to produce different monomers and, in addition, the \u00e2\u20ac\u0153common goods\u00e2\u20ac\u009d. Furthermore,
\n there is no evidence of ribozymes capable of synthesizing nucleotides from scratch;
\n the chemistry of the RNA catalysis, as revealed so far, is not very encouraging in
\n this respect. A possible solution for this conundrum is that monomers and other common
\n goods (e.g. amino acids and sugars) could be initially produced in abiotic reactions
\n [1\u00e2\u20ac\u201c5]. Only later, step by step, the first replicating entities may have learned to
\n synthesize nucleotides. Syntheses of nucleobases and amino acids were recently demonstrated
\n in the solutions that contained formamide or urea and in the presence of UV-light,
\n see [6,7] for reviews. Environments with high levels of amides\/urea could be envisioned
\n on the primordial Earth [6,8,9]. The hypothesis of abiotic origin of monomers got
\n a major boost after Sutherland, Powner and their co-workers succeeded in synthesizing
\n nucleotides from scratch in geologically plausible, one-pot settings [10,11]. In addition,
\n these authors have shown that natural nucleotides were particularly UV-stable, so
\n that their relative fraction selectively increased under UV illumination [10], in
\n support of earlier theoretical predictions [12]. In such a case, the very first replicators
\n would require only catalytic abilities of assembling abiotically formed monomers \u00e2\u20ac\u201c
\n a task that should have been feasible for ribozymes. Hence, scenarios of \u00e2\u20ac\u0153abiotic
\n syntheses\u00e2\u20ac\u009d match the simplified approach of K\u00c3\u00b6nny? and co-workers in that they imply
\n only few catalytic activities. In a framework of such scenarios, however, an essential
\n source of monomers for replication would be the decay of other replicators. Furthermore,
\n the abilities to accelerate this decay by cleaving neighboring sequences (which would
\n correspond to a reversion of the assembly reaction) as well as to use the fragments
\n for building the own \u00e2\u20ac\u0153body\u00e2\u20ac\u009d would be extremely advantageous. A scenario of \u00e2\u20ac\u0153abiotic
\n syntheses\u00e2\u20ac\u009d, of course, would require a separate model that would differ from the model
\n in the given manuscript. Still, in the view of anticipated importance of replicator
\n decay\/cleavage, an analysis of the present model in relation to the decay processes,
\n namely a consideration of the model outcome as a function of decay parameters (currently
\n absent from the manuscript) might be of use for readers.\n <\/p>\n
\n requires a lot more different types of catalysts than postulated in our model. However,
\n we are also sure that the only way such a metabolically competent ribozyme set could
\n have evolved is through the retroevolutionary mechanism explained in some detail elsewhere
\n [20\u00e2\u20ac\u201c21], which must have started from abiotiocally produced monomers at its very beginning,
\n exactly as the Reviewer suggests. We have inserted a paragraph into the Background
\n section pointing this out explicitly and citing the relevant literature.<\/em><\/p>\n
\n its neighborhood. Without such a figure, the sentence \u00e2\u20ac\u0153For a replication event to
\n occur the focal replicator s<\/em> must be complemented by all three different enzymatically active molecules in its
\n metabolic neighborhood (MET(h,s<\/em>), the set of h<\/em> sites concentric on the site of the focal replicator s<\/em>)\u00e2\u20ac\u009d is not quite clear.\n <\/p>\n
\n the product and \u00e2\u20ac\u0153catching\u00e2\u20ac\u009d the next substrate for catalysis\u00e2\u20ac\u009d. The whole section on
\n sub-additive effects is rather incomprehensible and showed be re-written in a more
\n clear way.\n <\/p>\n
\n be defined as one of assumptions of the model. Generally, it is possible to imagine
\n that unfolding could proceed concurrently with replication. That is how replication
\n occurs in our cells.\n <\/p>\n
\n of RNA molecules on the basis of first principles, but note that our postulate of
\n the temporal separation of the two processes is in fact a worst-case assumption: the
\n chance of catalytically active, low-energy folds to be replicated is small. Therefore
\n if this assumption has any effect on the results, then it is negative, but we actually
\n think that changing it may not alter the results in the qualitative sense.<\/em><\/p>\n
\n 1929, pp. 3\u00e2\u20ac\u201c10.\n <\/p>\n
\n USA, 31 (1945) 153\u00e2\u20ac\u201c157.\n <\/p>\n
\n NJ, 1973.\n <\/p>\n
\n (1999) 424\u00e2\u20ac\u201c431.\n <\/p>\n
\n of ribose, ribonucleosides, and RNA, Acc Chem Res, 45 (2012) 2025\u00e2\u20ac\u201c2034.\n <\/p>\n
\n origin of life, Phys Life Rev, 9 (2012) 84\u00e2\u20ac\u201c104.\n <\/p>\n
\n of first cells at terrestrial, anoxic geothermal fields, Proc Natl Acad Sci U S A,
\n 109 (2012) E821-830.\n <\/p>\n
\n role of energy in the emergence of biology from chemistry, Orig Life Evol Biosph,
\n 42 (2012) 459\u00e2\u20ac\u201c468.\n <\/p>\n
\n in prebiotically plausible conditions, Nature, 459 (2009) 239\u00e2\u20ac\u201c242.\n <\/p>\n
\n assembly of purine precursors in water, J Am Chem Soc, 132 (2010) 16677\u00e2\u20ac\u201c16688.\n <\/p>\n
\n the beginning of life: selection of the first oligonucleotide-like polymers by UV
\n light, BMC Evol Biol, 3 (2003) 12.\n <\/p>\n","protected":false},"excerpt":{"rendered":"