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Quantitative Analysis of Glycine Oligomerization by Ion-Pair Chromatography

  • Thomas D. Campbell
    Thomas D. Campbell
    Department of Chemistry, Saint Louis University, 3501 Laclede Avenue, St. Louis, Missouri 63103 United States
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  • Rio Febrian
    Rio Febrian
    Department of Chemistry, Saint Louis University, 3501 Laclede Avenue, St. Louis, Missouri 63103 United States
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  • Holly E. Kleinschmidt
    Holly E. Kleinschmidt
    Department of Chemistry, Saint Louis University, 3501 Laclede Avenue, St. Louis, Missouri 63103 United States
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  • Kevin A. Smith
    Kevin A. Smith
    Department of Chemistry, Saint Louis University, 3501 Laclede Avenue, St. Louis, Missouri 63103 United States
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  • Paul J. Bracher*
    Paul J. Bracher
    Department of Chemistry, Saint Louis University, 3501 Laclede Avenue, St. Louis, Missouri 63103 United States
    *E-mail: [email protected]
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    Orcidhttp://orcid.org/0000-0001-5769-8364
Cite this: ACS Omega 2019, 4, 7, 12745–12752
Publication Date (Web):July 26, 2019
https://doi.org/10.1021/acsomega.9b01492

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Abstract

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This paper describes a method for the quantitative analysis of mixtures of glycine and its oligomers by ion-pair high-performance liquid chromatography (IP-HPLC), with a particular focus on applications in origins-of-life research. We demonstrate the identification of glycine oligomers (Glyn) up to 14 residues long—the approximate detectable limit of their solubility in water—and measurement of the concentration of these species in the product mixture of an oligomerization reaction. The molar response factors for higher oligomers of glycine—which are impractical to obtain as pure samples—are extrapolated from direct analysis of pure standards of n = 3–6, which established a clear linear trend. We compare and contrast our method to those in previous reports with respect to accuracy and practicality. While the data reported here are specific to the analysis of oligomers of glycine, the approach should be applicable to the design of methods for the analysis of oligomerization of other amino acids.

Introduction

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The investigation of systems for the efficient synthesis of polypeptides in prebiotically relevant conditions is a major focus of origins-of-life research. Enlivened by Miller’s seminal experiment showing the synthesis of amino acids from a simulated Hadean atmosphere, researchers have studied the condensation of amino acids to form peptides in a variety of prospective prebiotic conditions. (1−3) Most proposed prebiotic syntheses of oligopeptides from amino acids can be classified into one or more of the following approaches: (i) catalysis by salts or surfaces at low water activity, (4−22) (ii) coupling mediated by stoichiometric reagents, (23−27) (iii) strand elongation via acyl-transfer reactions, (28−31) (iv) dry-downs and thermal/environmental cycling, (10,28,32−34) and (v) reactions driven by high-energy sources, like UV light or simulated asteroid impacts (see Figure 1). (35−39) Glycine is the most popular substrate for these studies because of its presumed prebiotic abundance and its simplicity—it lacks a side chain and is achiral; thus, no branched isomers or stereoisomers will form as products. (40,41)

Figure 1

Figure 1. Prebiotically feasible methods for the condensation of amino acids into peptides. Five general approaches to the synthesis of oligopeptides include the use of catalytic salts or surfaces in the dry state, the use of stoichiometric coupling agents, elongation by acyl-transfer reactions, condensation through dry-downs or wet–dry environmental cycling, and reactions driven by sources of high energy, like UV light or shock impacts.

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Justification

Despite the popularity of amino-acid polymerizations—particularly of glycine—there is no standard approach to the analysis of their product mixtures. Often, the various methods employed are described in minimal experimental detail, and their underlying assumptions are overlooked. In this paper, we contrast the performance and limitations of our method versus those previously reported, with the goal of allowing future investigators to make informed decisions about how to analyze mixtures of oligopeptides and report yields in a manner that allows the meaningful comparison of results across the field.

Background

Prebiotic synthesis focuses on the conversion of simple feedstocks available on the early Earth into more complex, functional molecules and systems. For the condensation of amino acids, it is generally assumed to be advantageous to generate longer oligomers in higher yields with higher conversion of monomer into products. The motivating ideas are that (i) higher yields and conversions correspond to more efficient processes and (ii) longer peptides will have a greater chance of exhibiting the functional properties of proteins observed in biochemistry. The specific preference of a synthesis for one product over others may also be advantageous, though arguments can be made for the value of variety in polydisperse mixtures. Cyclic dipeptides (2,5-diketopiperazines, or DKPs) are generally regarded as undesirable “dead-ends” in these syntheses, as their lack of free amino and carboxyl groups limits their reactivity and, for many polymerizations, essentially removes amino acids from the reactive pool of building blocks. (42−44) An important aspect of evaluating and comparing proposed prebiotic syntheses of polypeptides is the characterization of the product mixtures. The general methods most commonly reported for these analyses are NMR spectroscopy, mass spectrometry (MS), and chromatography.
NMR spectroscopy can be used qualitatively to monitor the formation of amide bonds during amino-acid condensations. (34,45) We and others have used NMR spectroscopy quantitatively for applications like analyzing the hydrolysis of dipeptides of glycine and alanine, (46) but the technique becomes increasingly unsuitable for longer oligomers. Even the relatively short and simple oligomers Gly1–6 have overlapping signals that prevent accurate quantitative analysis of their mixtures (see Figure S17 in the Supporting Information).
Various MS techniques have been used to characterize the products of oligomerization reactions. MS methods are generally regarded as qualitative means of establishing the presence of various oligomers; the intensities of peaks are unreliable for measuring molecular concentrations, as peak intensities will also depend on each molecule’s propensity to ionize and fragment. Parker et al. used ultraperformance liquid chromatography paired with quadrupole-traveling wave ion-mobility spectrometry and time-of-flight MS (UPLC-Q-TWIMS-TOF-MS) to analyze the dipeptides produced in Miller–Urey experiments. (47) Rodriguez-Garcia et al. used matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) MS to identify the presence of oligomers up to Gly20. (34) Forsythe et al. recently used liquid chromatography–ion-mobility spectrometry–tandem MS (LC–IM–MS/MS) to identify mixed oligomers of Gly, Ala, Leu, and glycolic acid up to n = 8. (48) Advances are being made in improving MS methods to provide reliable quantitative data, (49) but ionization and fragmentation are not the only barriers to the application of MS to the analysis of oligopeptides. Many prebiotic syntheses employ dry-down conditions with relatively high concentrations of salts as simulations of evaporating pools of “prebiotic soups”. (21,41,50,51) The charged/zwitterionic nature of amino acids and peptides makes them difficult to separate from other ions (i.e., to de-salt them), and high salt is known to adversely affect a number of MS methods—limiting spectral quality, reducing quantitative accuracy, and potentially damaging the detector components of spectrometers. (52)
Chromatographic methods—sometimes used in conjunction with MS—have been the most common methods for the analysis of mixtures of peptide oligomers. Sugahara and Mimura as well as Fujimoto et al. used gas chromatography–MS (GC–MS) for the analysis of product mixtures from pressure-induced oligomerization of Ala. (35,36) The analytes were derivatized with isopropanol and trifluoroacetic anhydride to produce N-trifluoroacetic acylated-(Ala)n-O-isopropyl esters. Only small oligomers of Alan were formed, and the authors note that this method is limited to Alan oligomers of n ≤ 3, possibly because longer oligomers are insufficiently volatile for the analysis by GC.
Derivatization involves the functionalization of analytes with moieties that aid their detection. These procedures operate on the assumption that the oligomers present will react with the detection label with quantitative yield and that each tagged oligomer will have the same molar absorptivity (unless individual standards are tagged and analyzed as well). In-line tagging methods require LC systems with greater sophistication than may be accessible to some groups. Kitadai and co-workers used the method of Torres et al. for the quantitative analysis of oligomers of Glyn up to n = 6 using HPLC on a cation-exchange column with post-column derivatization by o-phthalaldehyde and fluorescence detection. (4−6,53) Fuchida and co-workers used the same method for the analysis of their product mixtures with oligomers up to Gly3. (19)
Ion-pair high-performance liquid chromatography (IP-HPLC) has proven in many studies to be an effective method for the separation of various oligomers of glycine. (7,11−14,16,20,21,34,38,39) In most of these studies, the Glyn product mixtures were limited to n ≤ 6; thus, analytical standards were commercially available. Ohara et al. employed the method of Rode and co-workers (21,54) in using HPLC with hexanesulfonate as an ion-pair reagent to measure oligomers up to Gly6 by UV detection and then used LC with a perfluorinated surfactant to observe Gly7–10 with detection by MS. (39)
Dalai et al. produced oligomers up to Gly6 in their condensations and used IP-HPLC for the primary analysis of the products. (13) To quantify the short oligomers of Glyn (n ≤ 3), they compared the UV response of the products to analytical standards. For the longer oligomers (n ≥ 4), the authors derivatized the oligomers with 2,4-dinitrophenyl groups using Sanger’s reagent and analyzed the products by reverse-phase HPLC.
Rodriguez-Garcia et al. extended an IP-HPLC method reported by Rode and co-workers to quantify total combined yields of oligomers up to Gly14. (21,34) They calculated the total yield of an oligomerization reaction as the proportion of Gly converted into Gly≥2 (excluding DKP) based on “the mean absorbance per glycine unit in the larger standards, which was observed to become approximately constant >3-mer”.
Yu et al. used hydrophilic interaction liquid chromatography for the quantification of depsipeptides and short oligomers of glycine. (55) They analyzed standards of Glyn where n = 1–3 and hydroxyacid-N-capped oligomers of glycine and operated under the assumption that the trend in extinction coefficients extends to higher oligomers.

Results

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Measurement/Extrapolation of Molar Response Factors (fn) for Each Glyn

To determine whether there was a relationship between oligomer length and molar UV response (fn) that could be used to extrapolate values of fn for higher oligomers, we obtained commercial samples of Gly1–6 and a custom order of Gly8. We also ordered Gly10, but the vendor was unable to synthesize a pure sample. IP-HPLC analysis of the Gly1–6 samples showed them to be free of detectable impurities, whereas the Gly8 sample had detectable quantities of other Glyn oligomers (see Figure S1). As such, we relied on samples of Gly1–6—and not Gly8—in our extrapolation of molar response factors for higher oligomers.
The IP-HPLC chromatograms plot absorbance (in units of mV, from detector signal) versus retention time as analytes elute from the column. We measured the UV response (An, peak area) for each Glyn standard at varying concentrations to calculate the molar response factors (fn) of each oligomer (Figure 2). Equation 1 relates the UV response to the number of moles of standard (mn) injected per analyte
(1)

Figure 2

Figure 2. (A) Overlaid chromatograms of standard solutions of Gly4 of varying concentrations, with injections of 5 μL and detection at 195 nm. (B) Plot of the UV response vs the number of molecules of Gly4 injected. The slope of the line equals the molar response factor (fn) for Gly4, in accordance with eq 1. Each point represents the mean average of three standard samples of the corresponding concentration, and the errors bars represent 95% confidence intervals.

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We plotted the values of fn versus oligomer length for the Gly1–6 standards and generated least-squares regression lines through the first three points, last four points, and all six points (Figure 3). All three lines had similar slopes and intercepts, which surprised us for the shortest oligomers, which we hypothesized could have very different absorbances. Of these three curves, the line fit to the Gly3–6 data most accurately models the measured values of the longest standards within the experimental error of the measurements (Figure 3, Table 1).

Figure 3

Figure 3. Plot of molar response factor (fn) at 195 nm vs oligomer length for standards of oligomers of glycine (Glyn, n = 1–6), with least-squares linear regression curves plotted through n = 1–6 (red), n = 1–3 (blue), and n = 3–6 (green). The error bars represent 95% CIs for the response factors, based on three measurements obtained independently from the slopes of linear calibration curves constructed for each oligomer, as for Gly4 in Figure 2B. Note the small differences in the least-squares linear regression curves; the green curve (n = 3–6) most accurately predicts the measured values of the longest oligomers within the experimental error of the measurements, and as such, it was used to extrapolate the values of fn for Gly>7 employed to determine yields in subsequent experiments (Table 1).

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Table 1. Molar Response Factors (fn) for Oligomers of Glycine (Glyn) from n = 1 to 14a
 response factor (V·s·mol–1 × 1015)
oligomer Glynmeasured fncalculated fn(1–3)calculated fn(3–6)calculated fn(1–6)
15.8 ± 0.29–136–29
2270 ± 6263184263
3513 ± 29516504555
4813 ± 35770823847
51137 ± 4102411431139
61470 ± 27127714621431
7 153117821723
8 178421012015
9 203824212307
10 229227412599
11 254530602891
12 279933803183
13 305336993475
14 330640193768
15 356043384060
a

Values measured from commercial standards appear in the second column, while values calculated from the three linear regression curves shown in Figure 3 appear in the rightmost columns. The bolded values of fn are those used in our determination of yields of oligomers in Glyn syntheses.

From this regression curve for Gly3–6, we extrapolated the molar response factor (fn) values for Gly7–14 (Table 1). With these values in hand, eq 1 is used to determine the concentration of each Glyn oligomer in a mixture separated by IP-HPLC. We validated the method by using it to verify the concentration of oligomers in a mixed standard to demonstrate that the oligomers did not interfere with each other’s measurement (see Figure S10 in the Supporting Information). We also measured a molar response factor for Gly8 from the impure commercial sample by correcting f8 to account for the measurable Gly6, Gly7, and Gly9 impurities in the sample (details in the Supplemental Experimental section of the Supporting Information). This corrected value for f8 was simply used as a “check standard” for the extrapolation model described above and was not used to extrapolate higher values of fn.

Characterization of Prebiotic Oligomerizations

As a final demonstration of the utility of the method, we applied it to the analysis of an actual condensation reaction that produced a mixture of oligoglycines under conditions reported by Cronin and co-workers. (34) We prepared three identical 4.0 mL aqueous solutions of 87.5 mM Gly, 250 mM NaCl, and 25 mM NaOH. The vials were placed on a hot plate maintained at 130 °C for 12 h and left open to evaporate to dryness during the heating period. The product was allowed to cool and subsequently dissolved in 4.0 mL of 0.1% trifluoroacetic acid (TFA) in water at room temperature for analysis by the IP-HPLC method described above. We determined the combined yield of all of the linear oligomers of glycine (Gly≥2) to be 49.5 ± 2.0% (95% confidence interval, based on the measurement of three samples, see Figure 4 and Table S3 in the Supporting Information). Cronin reported a yield of “ca. 45%” in an identical experiment. (34)

Figure 4

Figure 4. IP-HPLC chromatogram of the product mixture from the oligomerization of glycine described in the Results section. The total yield of linear oligomers (based on initial glycine, excluding DKP as an undesirable product) was determined to be 49.5 ± 2.0% .

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Discussion

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We began from the IP-HPLC method for the analysis of oligoglycine originally reported by Rode and used by both Ohara and Cronin. (21,34,39) The technique appears to be limited by the solubility of Glyn oligomers in the running buffer. When we analyzed a commercial sample of poly(glycine) with molecular weight cutoff of approximately 5000 g/mol, the chromatogram comprised peaks that we felt comfortable integrating up to Gly14 (details available in the Supporting Information, Figure S19). The higher peaks faded into the baseline and broke in the pattern of having progressively longer differences in retention time from the previous oligomer. In the preparation of the polyglycine sample, some of the solid did not dissolve—likely higher oligomers that are insoluble or poorly/partially soluble. Cronin and co-workers noted similar behavior in their samples from the condensation of Gly. (34) Reanalysis of the solid by IP-HPLC found oligomers that were presumably saturated in the first sample. They also analyzed the undissolved solid by MALDI MS and identified oligomers up to Gly20. As noted previously, MS methods are useful for the qualitative determination of the presence of oligomers, but samples with high salt can be difficult to analyze quantitatively.
We attempted to modify the IP-HPLC method to enable quantitative analysis of longer oligomers by addition of water-miscible organic solvents, like acetonitrile, to the running buffer to improve the solubility of the longer Glyn species. However, in all attempts, the cosolvent drastically and unfavorably altered the retention times and resolution of the oligomers. We also attempted to optimize the separation by testing alkylsulfonates of different lengths (with C6, C8, and C10 alkyl chains) but returned to hexanesulfonate as the best option.
When optimizing conditions for the separation of oligoglycines, we paid particular focus to the separation of Gly3 and Gly4. For unknown reasons, these peaks run closer together than other oligomers. Their resolution vastly improved upon switching to a column with a lower particle size (3 vs 5 μm) and increasing the flow rate (up to 1.0 mL/min). Following these modifications, the method reported here can give near-baseline resolution of the linear Glyn oligomers (n ≥ 2), which compares favorably to previous separations (Figure 4). (34,55) Glycine and DKP coelute, but their mutual interference is not necessarily a significant limitation to the evaluation of prebiotic systems (see the section on Guidance for Reporting Yields, below).

Method Validation

The concentration of each Glyn oligomer in a sample is measured by integrating its peak in the chromatogram and dividing by the corresponding molar response factor measured or calculated from standards (Table 1). We rely on external standards because the chromatogram is already crowded with Glyn peaks, and the inclusion of an extra analyte would interfere with measurement of the oligomers.
To verify the accuracy of the method, we compared the total concentration of Gly (in all forms of Glyn) in a standard sample of mixed Glyn standards (n = 1–6) measured by both quantitative NMR spectroscopy and the IP-HPLC method described above. The concentrations measured by the two methods differed by just 3.2% (see the Supporting Information, Figure S17 and Table S2).

Guidance for Reporting Yields

Quantitative analysis provides useful information with respect to evaluating prebiotic syntheses, and in the context of oligoglycine synthesis, there have been a variety of approaches. Conversions and yields are the standard metrics of synthetic reactions. (56) In theory, the simplest approach to analyze the efficiency of oligomerization would be to measure the remaining Gly and calculate its conversion—the percentage of it consumed in the reaction, assuming that all of the consumed glycine was converted to higher oligomers. However, in practice, Gly often coelutes with other byproducts or—in the case of nonchromatographic techniques—interferes with the signal for other analytes, which prevents a quantitative measure of Gly alone. Additionally, such an approach would not penalize side reactions like pyrolysis of glycine or the formation of prebiotically undesirable byproducts, such as diketopiperizine (DKP). (57)
Yields of the individual Glyn oligomers—calculated from their UV responses—are more robust metrics for the evaluation of peptide syntheses than single values for the conversion of glycine. The molar response factors (fn) measured by our method permit the determination of the yield of each oligomer with a distinct peak. It is clear from comparison of the chromatogram for authentic low-molecular-weight (LMW) polyglycine and that of the prebiotic oligomerization reaction that there are products of the reaction that are not Glyn oligomers. We have not attempted to characterize these side products, but MS would be helpful in this regard. It is possible that unknown side products are coeluting with some of the Glyn oligomers, possibly inflating the calculated yields of one or more of the individual oligomers. Based on the characteristic stability of amino acids and peptides, as well as the sharpness of the peaks in our chromatograms, we believe the presence of these side products is small relative to the peptide oligomers expected as products of the reaction.

Assumptions and Limitations

Our method relies on the assumption that the trend in the molar UV response observed in our Glyn standards continues linearly through Gly14. An advantage of using isocratic LC is that the oligomers all elute in the same solvent. By analyzing the standards in the same solvent, we can ensure that there are no variations based on changes to the molar absorptivities of the analytes across a gradient of solvents. Reports in the literature disagree as to whether these effects are significant or not. (58,59) Furthermore, we operate under the assumption that any potential secondary structures that may form in longer oligomers do not significantly impact the UV absorption of those analytes. We also assume that no byproducts of the reaction are coeluting with the oligomers of glycine. And as with other methods that use external standards, our method functions on the assumption that the instrument is precise and reproducible in delivering consistent injection volumes, which is reasonable, given the reproducibility of the data obtained on our standards.
The biggest limitation of the method is the reliable quantification of products that are not soluble in water. The solubility of oligomers of glycine appears to decrease as the number of residues increases. If a sample of Glyn is completely soluble in the running buffer, the IP-HPLC method will permit separation and accurate quantitative analysis. A significant limitation is that if there is any remaining solid that does not dissolve, the quantitative analysis will be flawed, as the solid sample will contain an unknown amount of Glyn oligomers. Attempts to dissolve the remaining solid and subject it to a second analytical run will be frustrated for the least soluble, higher oligomers. Fortunately, the vast majority of glycine oligomerizations reported in the literature produce mixtures of Glyn suitable for quantitative analysis by IP-HPLC. Only a few reports generate high enough yields of longer oligomers to preclude their complete analysis. Researchers should be careful to note whether their samples dissolve completely when reporting Glyn products and their yields.
In the future, as syntheses become progressively better in terms of yielding longer oligomers, it will be increasingly important for the field to develop a technique for the convenient quantitative analysis of these compounds. In the absence of such a method, researchers could draw incorrect conclusions when comparing multiple systems on the basis of yield. For example, if a significant portion of the starting material is converted into insoluble products that are not included in the chromatographic analysis, then the total yield of oligomers will be artificially undercalculated. A system with a lower overall yield, but no insoluble products, might erroneously appear to have a higher yield than a comparable system that did generate insoluble Glyn oligomers. It appears that future techniques will require analyte derivatization and/or nonaqueous solvents to overcome the limitation of the solubility of Gly>14 in water, but the use of these solvents poses a challenge for the effective separation of all of the analytes in the product mixtures.

Context

We wish to be clear about what we believe to be the main contributions of this paper. The idea of condensing glycine and other amino acids has a long history in origins-of-life research, but the vast majority of studies only report the synthesis of Gly≤6. These studies determine yields by comparison to standard samples of these oligomers, which can be obtained commercially. Despite the long history of work in this field, amino-acid oligomerizations and polymerizations are still a very active area of research. Recently, several systems have “taken off” in terms of producing oligomers of n > 6. These successes have introduced the challenge of analyzing mixtures of Gly>6, as these compounds are not easily purchased or synthesized in sufficient mass and purity to use as standards. The inaccessibility of these standards necessitated the development of a means of extrapolating information about higher oligomers in order to characterize mixtures.
We were skeptical that the molar UV response factors of higher oligomers could be accurately extrapolated from Gly1–4. While the addition of each residue to longer oligomers (e.g., Gly12 to Gly13 to Gly14) places each chromophore in roughly the same environment, we expected addition of an extra residue to shorter oligomers to have less predictable consequences. After all, in shorter oligomers, the central residues are closer to the polar/charged C- and N-termini. The termini are also closer to each other in shorter oligomers, and we thought that it was unsound to assume that these differences would have no effect on absorptivity of the amide bonds. Therefore, we made it a point in this study to carefully measure the molar response factors of as many oligomers as possible to determine a proper calibration curve to extrapolate values of fn for longer oligomers. In a previous study of a different system, Codari et al. established that the response factors for oligo(lactic acid)—from hydrolysis of the parent polyester—are linear by measuring up to n = 9. (60) Similar to our approach described here, they used their data to extrapolate UV responses for higher oligomers. For the case of glycine oligomers, it appears that the extrapolation of fn values for Gly>7 is best obtained from a linear regression curve fitted to Gly3–6 (over Gly1–6 or Gly1–3) because of the smaller deviation of that line through the longer standards.
We also wish to be clear that IP-HPLC has existed for a long time. Rode first employed it for the analysis of glycine oligomerizations. (21) Cronin used it recently to analyze Gly≥6, (34) and in this paper, we report modifications to the method to improve resolution of peaks and ensure the quantitative rigor of the analysis. We are unaware of better separations of Gly3 and Gly4 by IP-HPLC.

Conclusions

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IP-HPLC offers a simple, robust, and convenient method for the quantitative analysis of condensation reactions of glycine. These reactions are of particular interest to the study of the origins of life. Over the years, research groups interested in the origins of life have employed a variety of methods to analyze condensation reactions of glycine and other amino acids. Yields in these systems are complicated metrics, as a wide mixture of products is produced. But having a simple, sensitive, and reliable method to quantify the products is vital when comparing multiple systems and studying experimental parameters. Although this method has limitations because of the solubility of products, it offers advantages compared to other methods with regard to improved resolution and robustness of the analysis of oligomers for which pure standards cannot be obtained. Oligomers higher than Gly15 have been synthesized in proposed prebiotic systems and detected by MS; thus, the development of methods that enable the quantitative analysis of these oligomers—which are practically insoluble in aqueous media—would be valuable for this field.

Methods

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Design

Our interest in studying amino-acid condensations, coupled with the variety of approaches to their analysis, motivated our search for a robust and reliable method to quantify glycine oligomerization reactions. We expect to produce higher oligomers of Glyn for which standards can be challenging to synthesize in high yield and purity. The lack of standards presents a problem for estimating the concentration of longer products in calculations of yield. We found previously reported methods to be lacking in one or more of the following characteristics: (i) they did not attempt to quantify higher oligomers, (ii) they extrapolated a trend for molar absorptivity based on a few short oligomers, with n < 4, or (iii) they did not describe the quantification of higher oligomers in detail. We were also troubled by the resolution of many of the reported separations, where overlapping peaks would hinder accurate determination of the UV response of individual oligomers in a sample. The separation of Gly3 and Gly4 can be particularly difficult. (34)
Our general approach entailed verifying, optimizing, and extending the IP-HPLC method for the separation of glycine oligomers reported by Rode and co-workers that was later modified by Cronin and co-workers. (21,34) Once the method produced chromatograms with acceptable resolution of peaks on our instrument, we were able to determine concentrations of each oligomer based on their UV responses and then use the data from standards to characterize reaction mixtures of glycine condensations under prebiotic conditions.

Materials, Safety, and General Procedures

All reagents, including glycine, oligomers of glycine up to Gly6, and LMW polyglycine were obtained from MilliporeSigma or VWR and their affiliate suppliers and were not purified further. TFA is a strong acid and care should be taken in its use. A standard of Gly8 was ordered for custom synthesis from Fisher Scientific USA. The purity of this sample was checked by IP-HPLC and found to be contaminated by other oligomers of glycine, including Gly, Gly6, Gly7, and Gly9 (Figure S1). As a result, we did not incorporate data collected on this sample of Gly8 into our model for the extrapolation of molar response factors (fn) of higher oligomers.
Standard solutions of each oligomer were prepared using a minimum of 10 mg of sample, and the solutions were prepared using a volumetric flask (of at least 50 mL) for accuracy. These solutions were diluted to five different concentrations using micropipettes, giving five individual standards for each oligomer (Figure S2). This procedure was repeated three different times for each oligomer of glycine, yielding three measurements for each oligomer at five different concentrations (Figures S3–S9). The three trials for each oligomer at each concentration were run with unique samples that were prepared individually for the determination of the molar response factor (fn).

Experimental Parameters of the IP-HPLC Method for the Quantification of Glyn

Oligomers of glycine were analyzed using IP-HPLC on a Shimadzu Prominence LC20-AR instrument equipped with a Phenomenex Luna C18 column (250 mm long × 4.6 mm diameter, 3 μm particle size). The mobile phase was an aqueous solution of 50 mM KH2PO4 and 7.2 mM sodium hexanesulfonate (SHS), adjusted to pH 2.5 by the addition of HPLC-grade 85% H3PO4. The mobile phase was used isocratically with a flow rate of 1.00 mL·min–1. When preparing a column for its first use, the mobile phase was passed through the column at 0.50 mL·min–1 for 12 h to establish an equilibrium with respect to adsorption of the SHS ion-pair reagent on the C18 stationary phase, in essence, establishing a modified stationary phase suitable for IP-HPLC. The column temperature was maintained at 30 °C by a column oven, and samples were injected in 5.0 μL aliquots by an autosampler to a 100 μL injection loop. The instrument is equipped with a dual-wavelength UV–vis detector, which was set to record absorbance at 195 and 214 nm. Our analysis relies exclusively on the data collected at 195 nm, where the analytes have higher molar absorptivity. With these experimental parameters, we achieved separation of all of the linear oligomers of glycine up to n = 14 in a commercial sample of LMW polyglycine (Figure S19).

Supporting Information

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The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.9b01492.

  • Material available: additional experimental details of the IP-HPLC method and practical notes for its application, NMR spectra of standards, calibration curves for each Glyn standard, additional IP-HPLC chromatograms, determination of limits of quantitation, and additional references (PDF)

Terms & Conditions

Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

Author Information

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  • Corresponding Author
  • Authors
    • Thomas D. Campbell - Department of Chemistry, Saint Louis University, 3501 Laclede Avenue, St. Louis, Missouri 63103 United States
    • Rio Febrian - Department of Chemistry, Saint Louis University, 3501 Laclede Avenue, St. Louis, Missouri 63103 United States
    • Holly E. Kleinschmidt - Department of Chemistry, Saint Louis University, 3501 Laclede Avenue, St. Louis, Missouri 63103 United States
    • Kevin A. Smith - Department of Chemistry, Saint Louis University, 3501 Laclede Avenue, St. Louis, Missouri 63103 United States
  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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This work was jointly supported by the National Science Foundation (NSF) and the National Aeronautics and Space Administration (NASA) Astrobiology Program, under the NSF Center for Chemical Evolution (CHE-1504217). T.D.C. was supported by the NASA Earth & Space Science Fellowship program (award #80NSSC17K0521). We thank Professor Ryan D. McCulla and John T. Petroff II for assistance with UV–vis spectroscopy. We also thank Professor Nicholas V. Hud, Professor Martha A. Grover, and the rest of the protopolypeptides team at the Center for Chemical Evolution for helpful discussions.

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This article references 60 other publications.

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    Polymns. of org. monomers including amino acids, nucleotides and monosaccharides are essential processes for chem. evolution of life. Since these reactions proceed with "dehydration" reactions, they are possibly promoted if combined with thermodynamically favorable "hydration" reactions of minerals and salts. To test the possibility, heating expts. were done of the simplest amino acid "glycine (Gly)" mixed with four simple anhyd. salts (MgSO4, SrCl2, BaCl2 and Li2SO4) at 140 °C up to 20 days. Gly polymn. was strongly promoted by mixing with the salts in the order of MgSO4 > SrCl2 > BaCl2 > Li2SO4. Up to 6-mer of Gly polymers were synthesized in the Gly-MgSO4 mixt., and a total yield of Gly polymers attained about 7% of the initial amt. of Gly by the 20 days heating. The total yield was about 200 times larger than that from the heating of Gly alone. XRD measurements of the Gly-MgSO4 mixt. revealed the generation of MgSO4 monohydrate during Gly polymn. These observations indicate that Gly polymn. was promoted by the salt hydrations through the hydration-dehydration interactions. Based on the observations, we tried to find a relationship between thermodn. characteristics of the interactions and the promotion effects of each salt on Gly polymn. It was found that the salts having lower hydration ΔrG0 (easier to hydrate) promote Gly polymn. more strongly. The relationship was used to est. promotion effects of simple oxide minerals on Gly polymn. The estns. were consistent with previous observations about the effects of these minerals on Gly polymn. The fact suggests that the hydration-dehydration interactions between amino acids and minerals are an important mechanism for amino acids' polymns. on minerals.
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    Polymn. of amino acids is a fundamentally important step for the chem. evolution of life. Nevertheless, its response to changing environmental conditions has not yet been well understood because of the lack of reliable quant. information. For thermodn., detailed prediction over diverse combinations of temp. and pH has been made only for a few amino acid-peptide systems. This study used recently reported thermodn. dataset for the polymn. of the simplest amino acid "glycine (Gly)" to its short peptides (di-glycine and tri-glycine) to examine chem. and structural characteristics of amino acids and peptides that control the temp. and pH dependence of polymn. Results showed that the dependency is strongly controlled by the intramol. distance between the amino and carboxyl groups in an amino acid structure, although the side-chain group role is minor. The polymn. behavior of Gly reported earlier in the literature is therefore expected to be a typical feature for those of α-amino acids. Equil. calcns. were conducted to examine effects of dissolved metals as a function of pH on the monomer-polymer equil. of Gly. Results showed that metals shift the equil. toward the monomer side, particularly at neutral and alk. pH. Metals that form weak interaction with Gly (e.g., Mg2+) have no noticeable influence on the polymn., although strong interaction engenders significant decrease of the equil. concns. of Gly peptides. Considering chem. and structural characteristics of Gly and Gly peptides that control their interactions with metals, it can be expected that similar responses to the addn. of metals are applicable in the polymn. of neutral α-amino acids. Neutral and alk. aq. environments with dissolved metals having high affinity with neutral α-amino acids (e.g., Cu2+) are therefore not beneficial places for peptide bond formation on the primitive Earth.
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    Glycine Polymerization on Oxide Minerals
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    It has long been suggested that mineral surfaces played an important role in peptide bond formation on the primitive Earth. However, it remains unclear which mineral species was key to the prebiotic processes. This is because great discrepancies exist among the reported catalytic efficiencies of minerals for amino acid polymns., owing to mutually different exptl. conditions. This study examd. polymn. of glycine (Gly) on nine oxide minerals (amorphous silica, quartz, α-alumina and γ-alumina, anatase, rutile, hematite, magnetite, and forsterite) using identical prepn., heating, and anal. procedures. Results showed that a rutile surface is the most effective site for Gly polymn. in terms of both amts. and lengths of Gly polymers synthesized. The catalytic efficiency decreased as rutile > anatase > γ-alumina > forsterite > α- alumina > magnetite > hematite > quartz > amorphous silica. Based on reported mol.-level information for adsorption of Gly on these minerals, polymn. activation was inferred to have arisen from deprotonation of the NH3+ group of adsorbed Gly to the nucleophilic NH2 group, and from withdrawal of electron d. from the carboxyl carbon to the surface metal ions. The orientation of adsorbed Gly on minerals is also a factor influencing the Gly reactivity. The examn. of Gly-mineral interactions under identical exptl. conditions has enabled the direct comparison of various minerals catalytic efficiencies and has made discussion of polymn. mechanisms and their relative influences possible Further systematic investigations using the approach reported herein (which are expected to be fruitful) combined with future microscopic surface analyses will elucidate the role of minerals in the process of abiotic peptide bond formation.
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    Peptide formation by the recently discovered salt-induced mechanism, the simplest possible prebiotic peptide generation process so far, has been studied with the example of some amino acids known to form by Miller or Fischer-Tropsch mechanisms in simulated primitive atm. expts. Valine and aspartic acid readily form peptides with glycine; self-condensation is obsd. for all acids except valine. Several findings give further indications toward the possible prebiotic relevance of the reaction: the obsd. preferential formation of peptide linkages, the shift from nature-irrelevant to nature-relevant peptide bonds in the presence of Cu(II) and the long conservation of optical purity in the reaction system. Addnl. data confirming the proposed reaction mechanism were obtained.
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    Peptide formation was enhanced by cyanate (I) added to hydroxylapatite or orthophosphates. When glycine is heated in the presence of hydroxylapatite or orthophosphates, diglycine (II) is formed. Addn. of inorg. I increased the yields of II, but its action as a condensing agent did not extend to all of the orthophosphates studied.
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    Huber, C.; Wächtershäuser, G. Peptides by Activation of Amino Acids with CO on (Ni,Fe)S Surfaces: Implications for the Origin of Life. Science 1998, 281, 670– 672,  DOI: 10.1126/science.281.5377.670
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    In expts. modeling volcanic or hydrothermal settings amino acids were converted into their peptides by use of copptd. (Ni,Fe)S and CO in conjunction with H2S (or CH3SH) as a catalyst and condensation agent at 100° and pH 7 to 10 under anaerobic, aq. conditions. These results demonstrate that amino acids can be activated under geochem. relevant conditions. They support a thermophilic origin of life and an early appearance of peptides in the evolution of a primordial metab.
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    Lambert, J.-F. Adsorption and Polymerization of Amino Acids on Mineral Surfaces: A Review. Origins Life Evol. Biospheres 2008, 38, 211– 242,  DOI: 10.1007/s11084-008-9128-3
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    A review. The present paper offers a review of recent (post-1980) work on amino acid adsorption and thermal reactivity on oxide and sulfide minerals. It is performed in the general frame of evaluating Bernal's hypothesis of prebiotic polymn. in the adsorbed state, but written from a surface scientist's point of view. After a general discussion of the thermodn. of the problem and exactly what effects surfaces should have to make adsorbed-state polymn. a viable scenario, we examine some practical difficulties in exptl. design and their bearing on the conclusions that can be drawn from extant works, including the relevance of the various available characterization techniques. We then present the state of the art concerning the mechanisms of the interactions of amino acids with mineral surfaces, including results from prebiotic chem.-oriented studies, but also from several different fields of application, and discuss the likely consequences for adsorption selectivities. Finally, we briefly summarize the data concerning thermally activated amide bond formation of adsorbed amino acids without activating agents. The reality of the phenomenon is established beyond any doubt, but our understanding of its mechanism and therefore of its prebiotic potential is very fragmentary. The review concludes with a discussion of future work needed to fill the most conspicuous gaps in our knowledge of amino acids/mineral surfaces systems and their reactivity.
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    Kumar, A.; Kamaluddin Oligomerization of glycine and alanine on metal(II) octacynaomolybdate(IV): role of double metal cyanides in prebiotic chemistry. Amino Acids 2012, 43, 2417– 2429,  DOI: 10.1007/s00726-012-1320-0
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    Oligomerization of glycine and alanine on metal(II) octacynaomolybdate(IV): role of double metal cyanides in prebiotic chemistry
    Kumar, Anand; Kamaluddin
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    Condensation reactions of amino acid (glycine and alanine) on the surface of metal(II) octacyanomolybdate(IV) (MOCMo) complexes are investigated using high-performance liq. chromatog. (HPLC) and electron spray ionizations-mass spectroscopy (ESI-MS). The series of MOCMo have been synthesized and the effect of outer sphere metal ions present in the MOCMo on the oligomerization of glycine and alanine at different temp. and time found out. Formation of peptides was obsd. to start after 7 days at 60 °C. Maximum yield of peptides was found after 35 days at 90 °C. It has been found that zinc(II) octacyanomolybdate(IV) and cobalt(II) were the most effective metal cations present in outer sphere of the MOCMo for the prodn. of high yield of oligomerized products. Surface area of MOCMo seems to play dominating parameter for the oligomerization of alanine and glycine. The results of the present study reveal the role of MOCMo in chem. evolution for the oligomerization of biomols.
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    Effects of metal ions and pH on the formation and decomposition rates of di- and tri-peptides in aqueous solution
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    The recent discovery of active deep-sea hydrothermal systems venting high-pH fluids suggests that the prebiotic chem. of the hydrothermal systems of early earth may have been more diverse than previously thought. To det. the most favorable conditions for prebiotic oligomerization, the effects of metal ions (Ca2+, Mg2+, Zn2+, Fe2+, Mn2+, and Cu2+) and pH on the formation and decompn. rates of glycylglycine (GlyGly), glycylglycylglycine (GlyGlyGly), and diketopiperazine (DKP) in aq. soln. were investigated. Glycine (Gly) solns. contg. metal ions were heated for 1-74 days at 140°C under various pH conditions and the samples were analyzed by high-performance liq. chromatog. GlyGly and DKP were produced in all samples regardless of the presence or absence of metal ions. GlyGly yields were higher under basic conditions (pH 9.8-9.9) than under acidic or neutral conditions. Moreover, GlyGly yields in the presence of Cu2+ and Zn2+ were higher than in the absence of Cu2+ and Zn2+; in the presence of metal ions other than Cu2+ and Zn2+, GlyGly yields were lower. The dimerization rate const. of Gly (k1) increased in the presence of Cu2+. GlyGlyGly was only produced in samples with Cu2+ and the yield was 5 times higher under basic conditions (pH 9.8) than under acidic (pH 3.4) or neutral (pH 7.1) conditions. However, other metal ions inhibited prebiotic peptide synthesis by catalyzing hydrolysis or chelation with amino acids. These results reflect the high stability of Cu2+ complexes with amino acids or peptides in the salt-induced peptide formation reaction, particularly at high pH. Although elongation of oligopeptides was not favored, formation of metal-amino acid or metal-short peptide chelates may have facilitated primitive biol. functions and expanded prebiotic reaction fields because of their mobility in the earth's early oceans.
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    Dalai, P.; Pleyer, H. L.; Strasdeit, H.; Fox, S. The Influence of Mineral Matrices on the Thermal Behavior of Glycine. Origins Life Evol. Biospheres 2017, 47, 427– 452,  DOI: 10.1007/s11084-016-9523-0
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    The Influence of Mineral Matrices on the Thermal Behavior of Glycine
    Dalai, Punam; Pleyer, Hannes Lukas; Strasdeit, Henry; Fox, Stefan
    Origins of Life and Evolution of Biospheres (2017), 47 (4), 427-452CODEN: OLEBEM; ISSN:0169-6149. (Springer)
    On the Hadean-Early Archean Earth, the first islands must have provided hot and dry environments for abiotically formed org. mols. The heat sources, mainly volcanism and meteorite impacts, were also available on Mars during the Noachian period. In recent work simulating this scenario, we have shown that neat glycine forms a black, sparingly water-sol. polymer ("thermomelanoid") when dry-heated at 200 °C under pure nitrogen. The present study explores whether relevant minerals and mineral mixts. can change this thermal behavior. Most expts. were conducted at 200 or 250 °C for 2 or 7 days. The mineral matrixes used were phyllosilicates (Ca-montmorillonites SAz-1 and STx-1, Na-montmorillonite SAz-1-Na, nontronite NAu-1, kaolinite KGa-1), salts (NaCl, NaCl-KCl, CaCl2, artificial sea salt, gypsum, magnesite), picritic basalt, and three Martian regolith simulants (P-MRS, S-MRS, JSC Mars-1A). The main anal. method employed was high-performance liq. chromatog. (HPLC). Glycine intercalated in SAz-1 and SAz-1-Na was well protected against thermomelanoid formation and sublimation at 200 °C: after 2 days, 95 and 79 %, resp., had either survived unaltered or been transformed into the cyclic dipeptide (DKP) and linear peptides up to Gly6. The glycine survival rate followed the order SAz-1 > SAz-1-Na > STx-1 ≈ NAu-1 > KGa-1. Very good protection was also provided by artificial sea salt (84 % unaltered glycine after 200 °C for 7 days). P-MRS promoted the condensation up to Gly6, consistent with its high phyllosilicate content. The remaining matrixes were less effective in preserving glycine as such or as peptides.
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    Porter, T. L.; Eastman, M. P.; Hagerman, M. E.; Price, L. B.; Shand, R. F. Site-specific Prebiotic Oligomerization Rreactions of Glycine on the Surface of Hectorite. J. Mol. Evol. 1998, 47, 373– 377,  DOI: 10.1007/pl00006394
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    Condensation reactions of the amino acid glycine on the surface of Cu(II)-exchanged hectorite are investigated using the technique of scanning force microscopy. Prebiotic conditions are simulated using alternate wetting and heating cycles. Concn., immobilization, and subsequent polymn. resulting in glycine oligomers are seen to occur primarily at step edges or faults in the topmost layer. Condensation reactions also occur within tiny micropores or defects in the topmost layer. These reactions are facilitated by the availability of intergallery metal cations at the step edges or pores in the surface region.
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    Porter, T. L.; Eastman, M. P.; Bain, E.; Begay, S. Analysis of peptides synthesized in the presence of SAz-1 montmorillonite and Cu2+ exchanged hectorite. Biophys. Chem. 2001, 91, 115– 124,  DOI: 10.1016/s0301-4622(01)00159-4
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    We have investigated the synthesis of oligopeptides contg. glycine and tyrosine in the presence of the clay minerals montmorillonite (non-exchanged, SAz-1) and Cu2+ exchanged hectorite. In both cases, homopolymers of the two amino acids are formed, as are mixed peptides. In the case of Cu2+ hectorite, mixed oligopeptides up to trimers are detected in small amts. For montmorillonite, heterogeneous oligopeptides up to hexamers are detected. Our expts. indicate montmorillonite is more effective in promoting oligopeptide formation than Cu2+ hectorite. Anal. of the oligopeptide sequences formed on the montmorillonite surfaces indicates preferential synthesis of certain Gly-Tyr sequences over others.
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    Imai, Ei-ichi; Honda, Hajime; Hatori, Kuniyuki; Brack, Andre; Matsuno, Koichiro
    Science (Washington, D. C.) (1999), 283 (5403), 831-833CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
    Oligomerization of a peptide was attempted in a flow reactor that simulated a submarine hydrothermal system. When fluid contg. glycine repeatedly circulated through the hot and cold regions in the reactor, oligopeptides were made from glycine. When divalent ions (such as copper ions) were added under acidic conditions, oligoglycine was elongated up to hexaglycine. This observation suggests that prebiotic monomers could have oligomerized in the vicinity of submarine hydrothermal vents on primitive Earth.
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    Paecht-Horowitz, M.; Berger, J.; Katchalsky, A. Prebiotic Synthesis of Polypeptides by Heterogeneous Polycondensation of Amino-acid Adenylates. Nature 1970, 228, 636– 639,  DOI: 10.1038/228636a0
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    Prebiotic synthesis of polypeptides by heterogeneous polycondensation of amino acid adenylates
    Paecht-Horowitz, M.; Berger, J.; Katchalsky, Aharon
    Nature (London, United Kingdom) (1970), 228 (5272), 636-9CODEN: NATUAS; ISSN:0028-0836.
    Alanyl adenylate underwent heterogeneous polymn. in the presence of montmorillonite of particle size 700 Å. The yield from 1 g alanyl adenylate in 24 hr was 10.3 mg peptide d.p. 9, 35.2 mg peptide d.p. 16, and 20 mg peptide d.p. 27. Many peptide units contained a terminal adenylic acid group as an ester between the amino acid and the adenylic OH. Alk. medium was necessary to dissoc. ammonium groups for polymn. to occur. Liberated adenylic acid was neutralized with NaOH. Illite similarly yielded peptides of d.p. 10-16.
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    Bujdák, J.; Le Son, H.; Rode, B. M. Montmorillonite Catalyzed Peptide Bond Formation: The Effect of Exchangeable Cations. J. Inorg. Biochem. 1996, 63, 119– 124,  DOI: 10.1016/0162-0134(95)00186-7
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    Montmorillonite catalyzed peptide bond formation: the effect of exchangeable cations
    Bujdak, Juraj; Son, Hoang Le; Rode, Bernd Michael
    Journal of Inorganic Biochemistry (1996), 63 (2), 119-124CODEN: JIBIDJ; ISSN:0162-0134. (Elsevier)
    The effect of exchangeable cations, namely, alkali and alk. metal, ammonium and aluminum ions, on montmorillonite (M) catalyzed peptide formation was investigated. Amino acid dimerization and peptide chain elongation proceed with relatively low yields on macroscopically swelling montmorillonites (Li-M, Na-M) due to redistribution and insufficient concn. of reactant mols. on the clay surface. Cyclic anhydride (CA) formation, proceeding by monomol. mechanism, is primarily affected by the accessibility of catalytic sites for dimer activation. Weaker sorbed exchangeable cations do not block catalytic sites, and thus favor CA formation.
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    Fuchida, S.; Masuda, H.; Shinoda, K. Peptide Formation Mechanism on Montmorillonite Under Thermal Conditions. Origins Life Evol. Biospheres 2014, 44, 13– 28,  DOI: 10.1007/s11084-014-9359-4
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    Peptide Formation Mechanism on Montmorillonite Under Thermal Conditions
    Fuchida, Shigeshi; Masuda, Harue; Shinoda, Keiji
    Origins of Life and Evolution of Biospheres (2014), 44 (1), 13-28CODEN: OLEBEM; ISSN:0169-6149. (Springer)
    The oligomerization of amino acids is an essential process in the chem. evolution of proteins, which are precursors to life on Earth. Although some researchers have obsd. peptide formation on clay mineral surfaces, the mechanism of peptide bond formation on the clay mineral surface has not been clarified. In this study, the thermal behavior of glycine (Gly) adsorbed on montmorillonite was obsd. during heating expts. conducted at 150 °C for 336 h under dry, wet, and dry-wet conditions to clarify the mechanism. Approx. 13.9 % of the Gly monomers became peptides on montmorillonite under dry conditions, with diketopiperazine (cyclic dimer) being the main product. On the other hand, peptides were not synthesized in the absence of montmorillonite. Results of IR anal. showed that the Gly monomer was mainly adsorbed via hydrogen bonding between the pos. charged amino groups and neg. charged surface sites (i.e., Lewis base sites) on the montmorillonite surface, indicating that the Lewis base site acts as a catalyst for peptide formation. In contrast, peptides were not detected on montmorillonite heated under wet conditions, since excess water shifted the equil. towards hydrolysis of the peptides. The presence of water is likely to control thermodn. peptide prodn., and clay minerals, esp. those with electrophilic defect sites, seem to act as a kinetic catalyst for the peptide formation reaction.
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    Shanker, U.; Bhushan, B.; Bhattacharjee, G.; Kamaluddin Oligomerization of Glycine and Alanine Catalyzed by Iron Oxides: Implications for Prebiotic Chemistry. Origins Life Evol. Biospheres 2012, 42, 31– 45,  DOI: 10.1007/s11084-012-9266-5
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    20
    Oligomerization of Glycine and Alanine Catalyzed by Iron Oxides: Implications for Prebiotic Chemistry
    Shanker, Uma; Bhushan, Brij; Bhattacharjee, G.; Kamaluddin
    Origins of Life and Evolution of Biospheres (2012), 42 (1), 31-45CODEN: OLEBEM; ISSN:0169-6149. (Springer)
    Iron oxide minerals are probable constituents of the sediments present in geothermal regions of the primitive earth. They might have adsorbed different org. monomers (amino acids, nucleotides etc.) and catalyzed polymn. processes leading to the formation of the first living cell. In the present work we tested the catalytic activity of three forms of iron oxides (Goethite, Akaganeite and Hematite) in the intermol. condensation of each of the amino acids glycine and L-alanine. The effect of zinc oxide and titanium dioxide on the oligomerization has also been studied. Oligomerization studies were performed for 35 days at three different temps. 50, 90 and 120°C without applying drying/wetting cycling. The products formed were characterized by HPLC and ESI-MS techniques. All three forms of iron oxides catalyzed peptide bond formation (23.2% of gly2 and 10.65% of ala2). The reaction was monitored every 7 days. Formation of peptides was obsd. to start after 7 days at 50°C. Maximum yield of peptides was found after 35 days at 90°C. Reaction at 120°C favors formation of diketopiperazine derivs. It is also important to note that after 35 days of reaction, goethite produced dimer and trimer with the highest yield among the oxides tested. We suggest that the activity of goethite could probably be due to its high surface area and surface acidity.
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    Rode, B. M.; Schwendinger, M. G. Copper-Catalyzed Amino Acid Condensation in Water—A Simple Possible Way of Prebiotic Peptide Formation. Origins Life Evol. Biospheres 1990, 20, 401– 410,  DOI: 10.1007/bf01808134
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    Bhushan, B.; Nayak, A.; Kamaluddin Role of manganese oxides in peptide synthesis: implication in chemical evolution. Int. J. Astrobiol. 2017, 16, 360– 367,  DOI: 10.1017/s1473550416000471
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    Role of manganese oxides in peptide synthesis: implication in chemical evolution
    Bhushan, Brij; Nayak, Arunima; Kamaluddin
    International Journal of Astrobiology (2017), 16 (4), 360-367CODEN: IJANFR; ISSN:1473-5504. (Cambridge University Press)
    During the course of chem. evolution the role of metal oxides may have been very significant in catalyzing the polymn. of biomonomers. The peptide bond formation of alanine (ala) and glycine (gly) in the presence of various oxides of manganese were performed for a period of 35 days at three different temps. 50, 90 and 120°C without applying drying/wetting cycling. The reaction was monitored every week. The products formed were characterized by high-performance liq. chromatog. and electrospray ionization-mass spectrometry techniques. Trace amt. of oligomers was obsd. at 50°C. Maximum yield of peptides was found after 35 days at 90°C. It is important to note that very high temps. of 120°C favored the formation of diketopiperazine derivs. Different types of manganese oxides [manganosite (MnO), bixbyite (Mn2O3), hausmannite (Mn3O4) and pyrolusite (MnO2)] were used as catalyst. The MnO catalyzed glycine to cyclic (Gly)2, (Gly)2 and (Gly)3, and alanine, to cyclic (Ala)2 and (Ala)2. Mn3O4 also produced the same products but in lesser yield, while Mn2O3 and MnO2 produced cyclic anhydride of glycine and alanine with a trace amt. of dimers and trimmers. Manganese of lower oxidn. state is much more efficient in propagating the reaction than higher oxidn. states. The possible mechanism of these reactions and the relevance of the results for the prebiotic chem. are discussed.
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    Beaufils, D.; Jepaul, S.; Liu, Z.; Boiteau, L.; Pascal, R. The Activation of Free Dipeptides Promoted by Strong Activating Agents in Water Does not Yield Diketopiperazines. Origins Life Evol. Biospheres 2016, 46, 19– 30,  DOI: 10.1007/s11084-015-9455-0
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    The Activation of Free Dipeptides Promoted by Strong Activating Agents in Water Does not Yield Diketopiperazines
    Beaufils, Damien; Jepaul, Sandra; Liu, Ziwei; Boiteau, Laurent; Pascal, Robert
    Origins of Life and Evolution of Biospheres (2016), 46 (1), 19-30CODEN: OLEBEM; ISSN:0169-6149. (Springer)
    The activation of dipeptides was studied in the perspective of the abiotic formation of oligopeptides of significant length as a requirement for secondary structure formation. The formation of piperazin-2,5-diones (DKP), previously considered as a dead end when activating free dipeptides, was shown in this work to be efficiently suppressed when using strong activating agents (e.g., carbodiimides). This behavior was explained by the fast formation of a 5(4H)-oxazolone intermediate at a rate that exceeds the time scale of the rotation of the peptide bond from the predominant trans-conformation into the cis-isomer required for DKP formation. No DKP was obsd. when using strong activating agents whereas phosphate mixed anhydrides or moderately activated esters were obsd. to predominantly yield DKP. The DKP side-reaction no longer constitutes a drawback for the C-terminus elongation of peptides. These results are considered as addnl. evidence that pathways involving strong activation are required to drive the emergence of living entities rather than close to equil. processes.
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    Ehler, K. W.; Orgel, L. E. N,N′-Carbonyldiimidazole-Induced Peptide Formation in Aqueous Solution. Biochim. Biophys. Acta, Protein Struct. 1976, 434, 233– 243,  DOI: 10.1016/0005-2795(76)90055-6
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    N,N'-carbonyldiimidazole-induced peptide formation in aqueous solution
    Ehler, K. W.; Orgel, L. E.
    Biochimica et Biophysica Acta, Protein Structure (1976), 434 (1), 233-43CODEN: BBPTBH; ISSN:0005-2795.
    N,N'-carbonyldiimidazole reacts with glycine in aq. imidazole buffers at 0° to yield N-[1-imidazolylcarbonyl]glycine, which condenses slowly to give oligopeptides.
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    Danger, G.; Boiteau, L.; Cottet, H.; Pascal, R. The Peptide Formation Mediated by Cyanate Revisited. N-Carboxyanhydrides as Accessible Intermediates in the Decomposition of N-Carbamoylamino Acids. J. Am. Chem. Soc. 2006, 128, 7412– 7413,  DOI: 10.1021/ja061339+
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    The Peptide Formation Mediated by Cyanate Revisited. N-Carboxyanhydrides as Accessible Intermediates in the Decomposition of N-Carbamoylamino Acids
    Danger, Gregoire; Boiteau, Laurent; Cottet, Herve; Pascal, Robert
    Journal of the American Chemical Society (2006), 128 (23), 7412-7413CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
    Similar to many ureas, N-carbamoylamino acids were shown to be hydrolyzed in aq. soln. through elimination mechanisms at close to neutral pH, the nucleophilic attack of water being a minor process. Two competing elimination mechanisms can take place involving either cyanate or isocyanate transient intermediates. Peptide formation was obsd. and attributed to the latter pathway through the intermediacy of amino acid N-carboxyanhydride (NCA). Eventually, cyanate and its precursors (including urea) unexpectedly behave as amino acid activating agents because of their ability in amino acid carbamoylation. Owing to its ability to generate a background prebiotic prodn. of NCAs on the primitive Earth, this reaction is suggested to have contributed to the origin of life process.
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    Leman, L.; Orgel, L.; Ghadiri, M. R. Carbonyl Sulfide-Mediated Prebiotic Formation of Peptides. Science 2004, 306, 283– 286,  DOI: 10.1126/science.1102722
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    Carbonyl Sulfide-Mediated Prebiotic Formation of Peptides
    Leman, Luke; Orgel, Leslie; Ghadiri, M. Reza
    Science (Washington, DC, United States) (2004), 306 (5694), 283-286CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
    Almost all discussions of prebiotic chem. assume that amino acids, nucleotides, and possibly other monomers were first formed on the Earth or brought to it in comets and meteorites, and then condensed nonenzymically to form oligomeric products. However, attempts to demonstrate plausibly prebiotic polymn. reactions have met with limited success. We show that carbonyl sulfide (COS), a simple volcanic gas, brings about the formation of peptides from amino acids under mild conditions in aq. soln. Depending on the reaction conditions and additives used, exposure of α-amino acids to COS generates peptides in yields of up to 80% in minutes to hours at room temp.
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    Kawamura, K.; Takeya, H.; Kushibe, T. Effect of condensation agents and minerals for oligopeptide formation under mild and hydrothermal conditions in related to chemical evolution of proteins. Adv. Space Res. 2009, 44, 267– 275,  DOI: 10.1016/j.asr.2009.03.027
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    Effect of condensation agents and minerals for oligopeptide formation under mild and hydrothermal conditions in related to chemical evolution of proteins
    Kawamura, Kunio; Takeya, Hitoshi; Kushibe, Takao
    Advances in Space Research (2009), 44 (2), 267-275CODEN: ASRSDW; ISSN:0273-1177. (Elsevier Ltd.)
    The role of condensation agents and minerals for oligopeptide formation was inspected to see whether minerals possess catalytic activity under mild and hydrothermal conditions. Under mild conditions, oligopeptide formation from neg. charged amino acids (Asp and Glu) using different minerals and the elongation of alanine oligopeptides ((Ala)2-(Ala)5) were attempted using apatite minerals. Oligo(Asp) up to 10 amino acid units from Asp were obsd. in the presence of 1-ethyl-3-(3)-dimethylaminopropyl carbodiimide (EDC). Notable influence of minerals was not detected for the oligo(Asp) formation. Oligo(Asp) was gradually degraded by the further incubation in the presence of EDC in both the absence and presence of minerals. The formation of oligo(Glu) was less efficient in the presence of carbonyldiimidazole. The elongation from (Ala)3, (Ala)4, and (Ala)5 and the formation of diketopiperazine from (Ala)2 proceeded immediately in the presence of EDC in the meantime of the sample prepns. In addn., it was unexpected that the disappearance of the products and the reformation of the reactants occurred by the further incubation for 24 h; for instance, (Ala)5 decreased but (Ala)4 increased with increasing the reaction time in the reaction of (Ala)4 with EDC. These facts suggest that the activation of the reactant amino acids or peptides immediately occurs. Under the simulated hydrothermal conditions, EDC did not enhance the formation of oligopeptides from Asp, Glu or Ala nor the spontaneous formation of (Ala)5 from (Ala)4.
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    Forsythe, J. G.; Yu, S.-S.; Mamajanov, I.; Grover, M. A.; Krishnamurthy, R.; Fernández, F. M.; Hud, N. V. Ester-Mediated Amide Bond Formation Driven by Wet-Dry Cycles: A Possible Path to Polypeptides on the Prebiotic Earth. Angew. Chem., Int. Ed. 2015, 54, 9871– 9875,  DOI: 10.1002/anie.201503792
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    Ester-Mediated Amide Bond Formation Driven by Wet-Dry Cycles: A Possible Path to Polypeptides on the Prebiotic Earth
    Forsythe, Jay G.; Yu, Sheng-Sheng; Mamajanov, Irena; Grover, Martha A.; Krishnamurthy, Ramanarayanan; Fernandez, Facundo M.; Hud, Nicholas V.
    Angewandte Chemie, International Edition (2015), 54 (34), 9871-9875CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Although it is generally accepted that amino acids were present on the prebiotic earth, the mechanism by which α-amino acids were condensed into polypeptides before the emergence of enzymes remains unsolved. Here, we demonstrate a prebiotically plausible mechanism for peptide (amide) bond formation that is enabled by α-hydroxy acids, which were likely present along with amino acids on the early earth. Together, α-hydroxy acids and α-amino acids form depsipeptides - oligomers with a combination of ester and amide linkages - in model prebiotic reactions that are driven by wet-cool/dry-hot cycles. Through a combination of ester-amide bond exchange and ester bond hydrolysis, depsipeptides are enriched with amino acids over time. These results support a long-standing hypothesis that peptides might have arisen from ester-based precursors.
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    A novel synthesis of polypeptides
    Oro, J.; Guidry, C. L.
    Nature (London, United Kingdom) (1960), 186 (), 156-7CODEN: NATUAS; ISSN:0028-0836.
    The product, obtained by heating glycinamide or glycinamide-HCl and NH4OH at 100° 20 hrs. in a closed vessel, was dialyzed until no low-mol.-wt. compds. remained and then lyophilized. The degree of polymerization was detd. by either the Sorensen formol titration in LiBr or a modified Van Slyke amino-N method (cf. CA 38, 5145). Pure cryst. glycinamide was 34% polymerized and gave a 75 mole-% yield of polymer, tannish white powder, insol. in H2O, sol. in concd; aq. LiBr, pos. biuret test, yielded only glycine on acid hydrolysis. Kinetic study showed that the initial reaction rate was sufficiently fast to be able to compete with side reactions. Data for the proof of the polyglycine structure by infrared spectra was given.
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    Nagayama, M.; Takaoka, O.; Inomata, K.; Yamagata, Y. Diketopiperazine-Mediated Peptide Formation in Aqueous Solution. Origins Life Evol. Biospheres 1990, 20, 249– 257,  DOI: 10.1007/bf01808107
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    Diketopiperazine-mediated peptide formation in aqueous solution
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    Origins of Life and Evolution of the Biosphere (1990), 20 (3-4), 249-57CODEN: OLEBEM; ISSN:0169-6149.
    Though diketopiperazines (DKP) are formed in most exptl. studies on prebiotic peptide formation, the mols. have not been considered in the studies of chem. evolution. Triglycine, tetraglycine, or pentaglycine are formed in an aq. soln. of glycine anhydride (a DKP)and glycine, diglycine, or triglycine, resp. A reaction of alanine with DKP resulted in the formation of glycylglycylalanine under the same conditions. The formation of the peptide bonds proceeds through the nucleophilic attack of an amino group of the amino acids or the oligoglycines on the DKP accompanied by ring-opening. The formation of glycine anhydride, di-, tri-, and tetraglycines was also obsd. in a mixed aq. soln. of urea and glycine in an open system to allow the evapn. of ammonia. A probable pathway is proposed for prebiotic peptide formation through diketopiperazine on the primitive Earth.
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    Takaoka, O.; Yamagata, Y.; Inomata, K. Diketopiperazine-Mediated Peptide Formation in Aqueous Solution II. Catalytic Effect of Phosphate. Origins Life Evol. Biospheres 1991, 21, 113– 118,  DOI: 10.1007/bf01809440
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    Diketopiperazine-mediated peptide formation in aqueous solution. II. Catalytic effect of phosphate
    Takaoka, O.; Yamagata, Y.; Inomata, K.
    Origins of Life and Evolution of the Biosphere (1991), 21 (3), 113-18CODEN: OLEBEM; ISSN:0169-6149.
    Phosphate catalyzed the condensation of diketopiperazine (DITP) with glycine (Gly) or oligoglycines (Glyn) to produce longer oligoglycines (Glyn+2). Formation of Gly4 from DKP (0.1 M) and Gly2 (0.1 M) in phosphate soln. of various concns. was investigated at a neutral pH at 41°. The yields of Gly4 increased almost linearly with the concn. of phosphate from 0.06 M to 0.24 M. The yield in 0.24 M phosphate soln. was approx. one hundred times as high as that in the absence of the phosphate, whereas in the case of Gly3 formation from DKP and Gly the effect of the phosphate was of ten times lower than in the former case. Orthophosphate was the most effective catalyst among the various kind of chems. tried in the present investigation including polyphosphates.
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    Lahav, N.; White, D.; Chang, S. Peptide Formation in the Prebiotic Era: Thermal Condensation of Glycine in Fluctuating Clay Environments. Science 1978, 201, 67– 69,  DOI: 10.1126/science.663639
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    Peptide formation in the prebiotic era: thermal condensation of glycine in fluctuating clay environments
    Lahav N; White D; Chang S
    Science (New York, N.Y.) (1978), 201 (4350), 67-9 ISSN:0036-8075.
    As geologically relevant models of prebiotic environments, systems consisting of clay, water, and amino acids were subjected to cyclic variations in temperature and water content. Fluctuations of both variables produced longer oligopeptides in higher yields than were produced by temperature fluctuations alone. The results suggest that fluctuating environments provided a favorable geological setting in which the rate and extent of chemical evolution would have been determined by the number and frequency of cycles.
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    Rohlfing, D. L. Thermal Polyamino Acids: Synthesis at Less Than 100 °C. Science 1976, 193, 68– 70,  DOI: 10.1126/science.935858
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    Thermal poly(amino acids): synthesis at less than 100°C
    Rohlfing, Duane L.
    Science (Washington, DC, United States) (1976), 193 (4247), 68-70CODEN: SCIEAS; ISSN:0036-8075.
    Thermally prepd. polyamino acids, regarded as models for prebiotic protein, typically have been synthesized at 120°-200°. In this study, 3 different sets of amino acid mixts. yielded material of relatively high-mol. wt. (mol. sieving and diffusion techniques) when heated for ≤81 days at 85°, 75°, and 65°. These temps., which today are generated by radiation from the sun in some terrestrial locales, probably were more common on the prebiotic earth than those above the b.p. of H2O. The results suggest that prebiotic polyamino acids were relatively common and widespread.
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    Rodriguez-Garcia, M.; Surman, A. J.; Cooper, G. J.; Suárez-Marina, I.; Hosni, Z.; Lee, M. P.; Cronin, L. Formation of oligopeptides in high yield under simple programmable conditions. Nat. Commun. 2015, 6, 8385,  DOI: 10.1038/ncomms9385
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    Formation of oligopeptides in high yield under simple programmable conditions
    Rodriguez-Garcia, Marc; Surman, Andrew J.; Cooper, Geoffrey J. T.; Suarez-Marina, Irene; Hosni, Zied; Lee, Michael P.; Cronin, Leroy
    Nature Communications (2015), 6 (), 8385CODEN: NCAOBW; ISSN:2041-1723. (Nature Publishing Group)
    Many high-yielding reactions for forming peptide bonds have been developed but these are complex, requiring activated amino-acid precursors and heterogeneous supports. Herein we demonstrate the programmable one-pot dehydration-hydration condensation of amino acids forming oligopeptide chains in around 50% yield. A digital recursive reactor system was developed to investigate this process, performing these reactions with control over parameters such as temp., no. of cycles, cycle duration, initial monomer concn. and initial pH. Glycine oligopeptides up to 20 amino acids long were formed with very high monomer-to-oligomer conversion, and the majority of these products comprised three amino acid residues or more. Having established the formation of glycine homo-oligopeptides, we then demonstrated the co-condensation of glycine with eight other amino acids (Ala, Asp, Glu, His, Lys, Pro, Thr and Val), incorporating a range of side-chain functionality.
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    Fujimoto, C.; Shinozaki, A.; Mimura, K.; Nishida, T.; Gotou, H.; Komatsu, K.; Kagi, H. Pressure-induced oligomerization of alanine at 25 °C. Chem. Commun. 2015, 51, 13358– 13361,  DOI: 10.1039/c5cc03665h
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    Pressure-induced oligomerization of alanine at 25°C
    Fujimoto, Chikako; Shinozaki, Ayako; Mimura, Koichi; Nishida, Tamihito; Gotou, Hirotada; Komatsu, Kazuki; Kagi, Hiroyuki
    Chemical Communications (Cambridge, United Kingdom) (2015), 51 (69), 13358-13361CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
    Pressure-induced oligomerization was found from high-pressure expts. at 25° on alanine powder soaked in its satd. aq. soln. The oligomerization to alanylalanine occurred at 5 GPa. The max. yields of alanylalanine and trialanine were, resp., 1.1 × 10-3 and 1.3 × 10-4 at 11 GPa.
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    Sugahara, H.; Mimura, K. Glycine oligomerization up to triglycine by shock experiments simulating comet impacts. Geochem. J. 2014, 48, 51– 62,  DOI: 10.2343/geochemj.2.0285
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    Glycine oligomerization up to triglycine by shock experiments simulating comet impacts
    Sugahara, Haruna; Mimura, Koichi
    Geochemical Journal (2014), 48 (1), 51-62CODEN: GEJOBE; ISSN:0016-7002. (Terra Scientific Publishing Co.)
    We conducted shock expts. simulating comet impacts to assess the feasibility of peptide synthesis by such a process. We used frozen mixt. of the amino acid glycine, water ice, and silicate (forsterite) as the starting material and applied impact shocks ranging from 4.8 to 26.3 GPa using a vertical propellant gun under cryogenic conditions (77 K). The results show that amino acid oligomerization up to trimers can be achieved. Further, linear peptides (dipeptide and tripeptide forms), which are important materials for the further elongation of peptide chains, were obtained in yields of one or two magnitudes greater than that of cyclic peptide form (diketopiperazine). These results contrast with those by Blank et al. (2001) for shock expts. of amino acid solns. at room temp., which showed the synthesis of a comparable amt. of diketopiperazines to that of the linear peptides. Thus, the existence of cryogenic conditions at the point of impact shock may be crit. for the formation of linear peptides. Our results demonstrate that comet impacts could have supplied a significant amt. of linear peptides on the early Earth and other extraterrestrial bodies.
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    Simakov, M. B.; Kuzicheva, E. A.; Mal’ko, I. L.; Dodonova, N. Y. Abiogenic synthesis of oligopeptides in solid state under action of vacuum ultraviolet light (100-200 nm). Adv. Space Res. 1996, 18, 61– 64,  DOI: 10.1016/0273-1177(96)00028-2
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    Abiogenic synthesis of oligopeptides in solid state under action of vacuum ultraviolet light (100-200 NM)
    Simakov, M. B.; Kuzicheva, E. A.; Mal'ko, I. L.; Dodonova, N. Ya.
    Advances in Space Research (1996), 18 (12, Life Sciences: Space and Mars Recent Results), 61-64CODEN: ASRSDW; ISSN:0273-1177. (Elsevier)
    Thin films contg. a mixt. of aliph. (glycine) and arom. (tryptophan or tyrosine) amino acids were exposed to vacuum UV radiation (VUV) with wavelengths 100-200 nm. Dipeptides (glycyltryptophan and glycyltyrosine) were synthesized under these conditions. The use of VUV and γ-radiation were compared. Polymn. is an essential step in prebiol. evolution and we have shown that this stage probably occurred during an early solar system period.
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    Otake, T.; Taniguchi, T.; Furukawa, Y.; Kawamura, F.; Nakazawa, H.; Kakegawa, T. Stability of Amino Acids and Their Oligomerization Under High-Pressure Conditions: Implications for Prebiotic Chemistry. Astrobiology 2011, 11, 799– 813,  DOI: 10.1089/ast.2011.0637
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    Stability of Amino Acids and Their Oligomerization Under High-Pressure Conditions: Implications for Prebiotic Chemistry
    Otake, Tsubasa; Taniguchi, Takashi; Furukawa, Yoshihiro; Kawamura, Fumio; Nakazawa, Hiromoto; Kakegawa, Takeshi
    Astrobiology (2011), 11 (8), 799-813CODEN: ASTRC4; ISSN:1531-1074. (Mary Ann Liebert, Inc.)
    The polymn. of amino acids leading to the formation of peptides and proteins is a significant problem for the origin of life. This problem stems from the instability of amino acids and the difficulty of their oligomerization in aq. environments, such as seafloor hydrothermal systems. We investigated the stability of amino acids and their oligomerization reactions under high-temp. (180-400°C) and high-pressure (1.0-5.5 GPa) conditions, based on the hypothesis that the polymn. of amino acids occurred in marine sediments during diagenesis and metamorphism, at convergent margins on early Earth. Our results show that the amino acids glycine and alanine are stabilized by high pressure. Oligomers up to pentamers were formed, which has never been reported for alanine in the absence of a catalyst. The yields of peptides at a given temp. and reaction time were higher under higher-pressure conditions. Elemental, IR, and isotopic analyses of the reaction products indicated that deamination is a key degrdn. process for amino acids and peptides under high-pressure conditions. A possible NH3-rich environment in marine sediments on early Earth may have further stabilized amino acids and peptides by inhibiting their deamination. Key Words: Origin of life-Peptide formation-Pressure-Deamination. Astrobiol. 11, 799-813.
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    Ohara, S.; Kakegawa, T.; Nakazawa, H. Pressure Effects on the Abiotic Polymerization of Glycine. Origins Life Evol. Biospheres 2007, 37, 215– 223,  DOI: 10.1007/s11084-007-9067-4
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    Pressure Effects on the Abiotic Polymerization of Glycine
    Ohara, Shohei; Kakegawa, Takeshi; Nakazawa, Hiromoto
    Origins of Life and Evolution of Biospheres (2007), 37 (3), 215-223CODEN: OLEBEM; ISSN:0169-6149. (Springer)
    Polymn. expts. were performed using dry glycine under various pressures of 5-100 MPa at 150°C for 1-32 days. The series of expts. was carried out under the assumption that the pore space of deep sediments was adequate for dehydration polymn. of pre-biotic mols. The products show various colors ranging from dark brown to light yellow, depending on the pressure. Visible and IR spectroscopy reveal that the coloring is the result of formation of melanoidins at lower pressures. High-performance liq. chromatog. and mass spectrometry analyses of the products show that: (1) glycine in all the exptl. runs oligomerizes from 2-mer to 10-mer; (2) the yields are dependent on pressure up to 25 MPa and decrease slightly thereafter; and (3) polymn. progressed for the first 8 days, while the amts. of oligomers remained const. for longer-duration runs of up to 32 days. These results suggest that pressure inhibits the decompn. of amino acids and encourages polymn. in the absence of a catalyst. The authors' results further imply that abiotic polymn. could have occurred during diagenesis in deep sediments rather than in oceans.
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    Trifonov, E. N. The Triplet Code from First Principles. J. Biomol. Struct. Dyn. 2004, 22, 1– 11,  DOI: 10.1080/07391102.2004.10506975
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    The triplet code from first principles
    Trifonov, Edward N.
    Journal of Biomolecular Structure & Dynamics (2004), 22 (1), 1-11CODEN: JBSDD6; ISSN:0739-1102. (Adenine Press)
    The temporal order ("chronol.") appearance of amino acids and their resp. codons on evolutionary scene is reconstructed. A consensus chronol. of amino acids was built on the basis of 60 different criteria each offering certain temporal order. After several steps of filtering the chronol. vectors were averaged resulting in the consensus order: Gly, Ala, Asp, Val, Pro, Ser, Glu, (Leu, Thr), Arg, (Ile, Gln, Asn), His, Lys, Cys, Phe, Tyr, Met, Trp. It revealed 2 important features: the amino acids synthesized in imitation expts. of S. Miller (1953, 1987) appeared 1st, whereas the amino acids assocd. with codon capture events came last. The reconstruction of codon chronol. was based on the above consensus temporal order of amino acids, supplemented by the stability and complementarity rules 1st suggested by M. Eigen and P. Schuster (1978), and on the earlier established processivity rule. At no point in the reconstruction was the consensus amino acid chronol. in conflict with these 3 rules. The derived genealogy of all 64 codons suggested several important predictions that were confirmed. The reconstruction of the origin and evolutionary history of the triplet code becomes, thus, a powerful research tool for mol. evolution studies, esp. in its early stages.
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    Longo, L. M.; Blaber, M. Protein design at the interface of the pre-biotic and biotic worlds. Arch. Biochem. Biophys. 2012, 526, 16– 21,  DOI: 10.1016/j.abb.2012.06.009
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    Protein design at the interface of the pre-biotic and biotic worlds
    Longo, Liam M.; Blaber, Michael
    Archives of Biochemistry and Biophysics (2012), 526 (1), 16-21CODEN: ABBIA4; ISSN:0003-9861. (Elsevier B.V.)
    A review. "Proteogenesis" (the origin of proteins) is a likely key event in the unsolved problem of biogenesis (the origin of life). The raw material for the very first proteins comprised the available amino acids produced and accumulated upon the early earth via abiotic chem. and phys. processes. A broad consensus is emerging that this pre-biotic set likely comprised Ala, Asp, Glu, Gly, Ile, Leu, Pro, Ser, Thr, and Val. A key question in proteogenesis is whether such abiotically-produced amino acids comprise a "foldable" set. Current knowledge of protein folding identifies properties of complexity, secondary structure propensity, hydrophobic-hydrophilic patterning, core-packing potential, among others, as necessary elements of foldability. None of these requirements excludes the pre-biotic set of amino acids from being a foldable set. Moreover, nucleophile and metal ion/mineral binding capabilities also appear present in the pre-biotic set. Properties of the pre-biotic set, however, likely restrict foldability to the acidophilic/halophilic environment.
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    Grover, M. A.; He, C. Y.; Hsieh, M.-C.; Yu, S.-S. A Chemical Engineering Perspective on the Origins of Life. Processes 2015, 3, 309– 338,  DOI: 10.3390/pr3020309
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    A chemical engineering perspective on the origins of life
    Grover, Martha A.; He, Christine Y.; Hsieh, Ming-Chien; Yu, Sheng-Sheng
    Processes (2015), 3 (2), 309-338CODEN: PROCCO; ISSN:2227-9717. (MDPI AG)
    Atoms and mols. assemble into materials, with the material structure detg. the properties and ultimate function. Human-made materials and systems have achieved great complexity, such as the integrated circuit and the modern airplane. However, they still do not rival the adaptivity and robustness of biol. systems. Understanding the reaction and assembly of mols. on the early Earth is a scientfic grand challenge, and also can elucidate the design principles underlying biol. materials and systems. This research requires understanding of chem. reactions, thermodn., fluid mechanics, heat and mass transfer, optimization, and control. Thus, the discipline of chem. engineering can play a central role in advancing the field. In this paper, an overview of research in the origins field is given, with particular emphasis on the origin of biopolymers and the role of chem. engineering phenomena. A case study is presented to highlight the importance of the environment and its coupling to the chem.
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    Brack, A.; Ehler, K. W.; Orgel, L. E. N,N′-Carbonyldiimidazole-Induced Diketopiperazine Formation in Aqueous Solution in the Presence of Adenosine-5′-Monophosphate. J. Mol. Evol. 1976, 8, 307– 310,  DOI: 10.1007/bf01739255
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    Brack, A.; Ehler, K. W.; Orgel, L. E.
    Journal of Molecular Evolution (1976), 8 (4), 307-10CODEN: JMEVAU; ISSN:0022-2844.
    3'(2')-O-Glycyladenosine 5'-monophosphate is an intermediate in the conversion of N-[imidazolyl-(1)-carbonyl]glycine to diketopiperazine in the presence of AMP. The significance of these observations to prebiotic chemistry is discussed.
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    Weber, A. L.; Orgel, L. E. The Formation of Peptides from the 2′(3′)-Glycyl Ester of a Nucleotide. J. Mol. Evol. 1978, 11, 189– 198,  DOI: 10.1007/bf01734480
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    The formation of peptides from the 2'(3')-glycyl ester of a nucleotide
    Weber, Arthur L.; Orgel, Leslie E.
    Journal of Molecular Evolution (1978), 11 (3), 189-98CODEN: JMEVAU; ISSN:0022-2844.
    2'(3')-O-(glycyl)-adenosine-5'-(O-methylphosphate), an analog of the 3'-terminus of aminoacylated tRNA, was synthesized. A 3.4M soln. of this compd. maintained at pH 8.2 yielded 5.5% diglycine and 11.5% diketopiperazine, in addn. to the hydrolysis products glycine and adenosine-5'-(O-methylphosphate). Under the same conditions glycine Et ester reacted much more slowly, but ultimately gave similar yields of diglycine and diketopiperazine. The aminolysis of 2'(3')-O-(glycyl)-adenosine-5'-(O-methylphosphate) by free glycine was relatively inefficient, but serine reacted 20 times more rapidly and yielded up to 50% of N-glycylserine. The prebiotic significance of these reactions is discussed.
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    Guo, C.; Holland, G. P. Alanine Adsorption and Thermal Condensation at the Interface of Fumed Silica Nanoparticles: A Solid-State NMR Investigation. J. Phys. Chem. C 2015, 119, 25663– 25672,  DOI: 10.1021/acs.jpcc.5b10236
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    Alanine Adsorption and Thermal Condensation at the Interface of Fumed Silica Nanoparticles: A Solid-State NMR Investigation
    Guo, Chengchen; Holland, Gregory P.
    Journal of Physical Chemistry C (2015), 119 (45), 25663-25672CODEN: JPCCCK; ISSN:1932-7447. (American Chemical Society)
    Studying the interface between biomols. and nanoparticles has attracted considerable attention in recent years since it has great significance in numerous fields including nanotechnol., biomineralization, cancer therapy, and origin of life. The authors present a thorough solid-state NMR study on alanine adsorption and thermal condensation on fumed silica nanoparticles. The structure and dynamics at the interface between alanine and fumed silica nanoparticles were probed with a combination of 1H, 13C, and 15N 1- and two-dimensional (2D) magic angle spinning (MAS) solid-state NMR methods at different alanine surface coverage and hydration levels. It is illustrated at high surface coverage both cryst. and adsorbed states of alanine exist in the samples while only adsorbed alanine is obsd. at low surface coverage (approx. a monolayer). At high hydration levels, the adsorbed alanine exhibits enhanced mobility, and both the carboxyl and amine group interact with mobile water mols. on the silica nanoparticle surface. At low hydration levels, the adsorbed alanine interacts with surface silanols via the protonated amine group and the carboxylate group. The thermal condensation of alanine on fumed silica nanoparticles was also studied, and alanine can undergo thermal condensation at ∼170° at the interface of fumed silica nanoparticles as confirmed by a battery of 13C and 15N 2-dimensional MAS solid-state NMR expts. By combining the adsorption and thermal condensation results, a possible mechanism for the silica surface-catalyzed thermal condensation reaction of alanine is proposed.
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    Campbell, T. D.; Hart, C. A.; Febrian, R.; Cheneler, M. L.; Bracher, P. J. The opposite effect of K+ and Na+ on the hydrolysis of linear and cyclic dipeptides. Tetrahedron Lett. 2018, 59, 2264– 2267,  DOI: 10.1016/j.tetlet.2018.04.073
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    The opposite effect of K+ and Na+ on the hydrolysis of linear and cyclic dipeptides
    Campbell, Thomas D.; Hart, Clara A.; Febrian, Rio; Cheneler, Mark L.; Bracher, Paul J.
    Tetrahedron Letters (2018), 59 (23), 2264-2267CODEN: TELEAY; ISSN:0040-4039. (Elsevier Ltd.)
    Potassium and sodium are generally considered inert 'spectator' ions for org. reactions. Here, we report rate consts. for the acid-promoted hydrolysis of the seven dipeptides of glycine (G) and alanine (A) and an unexpected pattern in how these rates differ in the presence of K+ and Na+. The linear dipeptides hydrolyze 12-18% percent slower in the presence of KCl vs. an equal concn. of NaCl, while the cyclic dipeptides hydrolyze 5-13% faster in the presence of KCl (all P-values < 0.025). We believe this is the first report of a general org. reaction-here, amide hydrolysis-for which some substrates react faster in the presence of K+ and others in Na+. The results offer a potential reason for life's mysterious universal selection of intracellular potassium over sodium.
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    Parker, E. T.; Zhou, M.; Burton, A. S.; Glavin, D. P.; Dworkin, J. P.; Krishnamurthy, R.; Fernández, F. M.; Bada, J. L. A Plausible Simultaneous Synthesis of Amino Acids and Simple Peptides on the Primordial Earth. Angew. Chem., Int. Ed. 2014, 53, 8132– 8136,  DOI: 10.1002/anie.201403683
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    A Plausible Simultaneous Synthesis of Amino Acids and Simple Peptides on the Primordial Earth
    Parker, Eric T.; Zhou, Manshui; Burton, Aaron S.; Glavin, Daniel P.; Dworkin, Jason P.; Krishnamurthy, Ramanarayanan; Fernandez, Facundo M.; Bada, Jeffrey L.
    Angewandte Chemie, International Edition (2014), 53 (31), 8132-8136CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
    Following his seminal work in 1953, Stanley Miller conducted an expt. in 1958 to study the polymn. of amino acids under simulated early Earth conditions. In the expt., Miller sparked a gas mixt. of CH4, NH3, and H2O, while intermittently adding the plausible prebiotic condensing reagent cyanamide. For unknown reasons, an anal. of the samples was not reported. We analyzed the archived samples for amino acids, dipeptides, and diketopiperazines by liq. chromatog., ion mobility spectrometry, and mass spectrometry. A dozen amino acids, 10 glycine-contg. dipeptides, and 3 glycine-contg. diketopiperazines were detected. Miller's expt. was repeated and similar polymn. products were obsd. Aq. heating expts. indicate that Strecker synthesis intermediates play a key role in facilitating polymn. These results highlight the potential importance of condensing reagents in generating diversity within the prebiotic chem. inventory.
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    Forsythe, J. G.; Petrov, A. S.; Millar, W. C.; Yu, S.-S.; Krishnamurthy, R.; Grover, M. A.; Hud, N. V.; Fernández, F. M. Surveying the sequence diversity of model prebiotic peptides by mass spectrometry. Proc. Natl. Acad. Sci. U.S.A. 2017, 114, E7652– E7659,  DOI: 10.1073/pnas.1711631114
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    Surveying the sequence diversity of model prebiotic peptides by mass spectrometry
    Forsythe, Jay G.; Petrov, Anton S.; Millar, W. Calvin; Yu, Sheng-Sheng; Krishnamurthy, Ramanarayanan; Grover, Martha A.; Hud, Nicholas V.; Fernandez, Facundo M.
    Proceedings of the National Academy of Sciences of the United States of America (2017), 114 (37), E7652-E7659CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
    The rise of peptides with secondary structures and functions would have been a key step in the chem. evolution which led to life. As with modern biol., amino acid sequence would have been a primary determinant of peptide structure and activity in an origins-of-life scenario. It is a commonly held hypothesis that unique functional sequences would have emerged from a diverse soup of proto-peptides, yet there is a lack of exptl. data in support of this. Whereas the majority of studies in the field focus on peptides contg. only one or two types of amino acids, here we used modern mass spectrometry (MS)-based techniques to sep. and sequence de novo proto-peptides contg. broader combinations of prebiotically plausible monomers. Using a dry-wet environmental cycling protocol, hundreds of proto-peptide sequences were formed over a mere 4 d of reaction. Sequence homol. diagrams were constructed to compare exptl. and theor. sequence spaces of tetrameric proto-peptides. MS-based analyses such as this will be increasingly necessary as origins-of-life researchers move toward systems-level investigations of prebiotic chem.
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    Urban, P. L. Quantitative mass spectrometry: an overview. Philos. Trans. R. Soc., A 2016, 374, 20150382,  DOI: 10.1098/rsta.2015.0382
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    Longo, L. M.; Blaber, M. Prebiotic protein design supports a halophile origin of foldable proteins. Front. Microbiol. 2014, 4, 418,  DOI: 10.3389/fmicb.2013.00418
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    Prebiotic protein design supports a halophile origin of foldable proteins
    Longo Liam M; Blaber Michael
    Frontiers in microbiology (2014), 4 (), 418 ISSN:1664-302X.
    There is no expanded citation for this reference.
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    Nelson, K. E.; Robertson, M. P.; Levy, M.; Miller, S. L. Concentration by evaporation and the prebiotic synthesis of cytosine. Origins Life Evol. Biospheres 2001, 31, 221– 229,  DOI: 10.1023/a:1010652418557
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    Concentration by evaporation and the prebiotic synthesis of cytosine
    Nelson, Kevin E.; Robertson, Michael P.; Levy, Matthew; Miller, Stanley L.
    Origins of Life and Evolution of the Biosphere (2001), 31 (3), 221-229CODEN: OLEBEM; ISSN:0169-6149. (Kluwer Academic Publishers)
    The efficient prebiotic synthesis of cytosine from urea and cyanoacetaldehyde (CA) has recently been claimed to be invalid on the basis of possible side reactions of the starting materials and the inapplicability of prebiotic syntheses using drying beach conditions. We therefore have investigated the synthesis of cytosine and uracil from urea and cyanoacetaldehyde at 100° under dry-down conditions, and in soln. at 4° and -20°. We find that cytosine is produced from the low temp. expts. more efficiently than calcd. from the Arrhenius extrapolation from higher temps., i.e., 60-120°. In addn., we find that CA dimer is as efficient as the monomer in cytosine synthesis. We also studied whether evapg. very dil. solns. of nonvolatile org. compds. will conc. according to theory. Solns. as dil. as 10-4 M conc. from pure water approx. according to theory. Similar solns. in 0.5 M NaCl have less than theor. concns. due to absorption, but concns. near dryness were very high.
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  • Abstract

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    Figure 1

    Figure 1. Prebiotically feasible methods for the condensation of amino acids into peptides. Five general approaches to the synthesis of oligopeptides include the use of catalytic salts or surfaces in the dry state, the use of stoichiometric coupling agents, elongation by acyl-transfer reactions, condensation through dry-downs or wet–dry environmental cycling, and reactions driven by sources of high energy, like UV light or shock impacts.

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    Figure 2

    Figure 2. (A) Overlaid chromatograms of standard solutions of Gly4 of varying concentrations, with injections of 5 μL and detection at 195 nm. (B) Plot of the UV response vs the number of molecules of Gly4 injected. The slope of the line equals the molar response factor (fn) for Gly4, in accordance with eq 1. Each point represents the mean average of three standard samples of the corresponding concentration, and the errors bars represent 95% confidence intervals.

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    Figure 3

    Figure 3. Plot of molar response factor (fn) at 195 nm vs oligomer length for standards of oligomers of glycine (Glyn, n = 1–6), with least-squares linear regression curves plotted through n = 1–6 (red), n = 1–3 (blue), and n = 3–6 (green). The error bars represent 95% CIs for the response factors, based on three measurements obtained independently from the slopes of linear calibration curves constructed for each oligomer, as for Gly4 in Figure 2B. Note the small differences in the least-squares linear regression curves; the green curve (n = 3–6) most accurately predicts the measured values of the longest oligomers within the experimental error of the measurements, and as such, it was used to extrapolate the values of fn for Gly>7 employed to determine yields in subsequent experiments (Table 1).

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    Figure 4

    Figure 4. IP-HPLC chromatogram of the product mixture from the oligomerization of glycine described in the Results section. The total yield of linear oligomers (based on initial glycine, excluding DKP as an undesirable product) was determined to be 49.5 ± 2.0% .

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  • References

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    This article references 60 other publications.

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      Kitadai, N. Dissolved Divalent Metal and pH Effects on Amino Acid Polymerization: A Thermodynamic Evaluation. Origins Life Evol. Biospheres 2017, 47, 13– 37,  DOI: 10.1007/s11084-016-9510-5
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      5
      Dissolved Divalent Metal and pH Effects on Amino Acid Polymerization: A Thermodynamic Evaluation
      Kitadai, Norio
      Origins of Life and Evolution of Biospheres (2017), 47 (1), 13-37CODEN: OLEBEM; ISSN:0169-6149. (Springer)
      Polymn. of amino acids is a fundamentally important step for the chem. evolution of life. Nevertheless, its response to changing environmental conditions has not yet been well understood because of the lack of reliable quant. information. For thermodn., detailed prediction over diverse combinations of temp. and pH has been made only for a few amino acid-peptide systems. This study used recently reported thermodn. dataset for the polymn. of the simplest amino acid "glycine (Gly)" to its short peptides (di-glycine and tri-glycine) to examine chem. and structural characteristics of amino acids and peptides that control the temp. and pH dependence of polymn. Results showed that the dependency is strongly controlled by the intramol. distance between the amino and carboxyl groups in an amino acid structure, although the side-chain group role is minor. The polymn. behavior of Gly reported earlier in the literature is therefore expected to be a typical feature for those of α-amino acids. Equil. calcns. were conducted to examine effects of dissolved metals as a function of pH on the monomer-polymer equil. of Gly. Results showed that metals shift the equil. toward the monomer side, particularly at neutral and alk. pH. Metals that form weak interaction with Gly (e.g., Mg2+) have no noticeable influence on the polymn., although strong interaction engenders significant decrease of the equil. concns. of Gly peptides. Considering chem. and structural characteristics of Gly and Gly peptides that control their interactions with metals, it can be expected that similar responses to the addn. of metals are applicable in the polymn. of neutral α-amino acids. Neutral and alk. aq. environments with dissolved metals having high affinity with neutral α-amino acids (e.g., Cu2+) are therefore not beneficial places for peptide bond formation on the primitive Earth.
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    6. 6
      Kitadai, N.; Oonishi, H.; Umemoto, K.; Usui, T.; Fukushi, K.; Nakashima, S. Glycine Polymerization on Oxide Minerals. Origins Life Evol. Biospheres 2017, 47, 123– 143,  DOI: 10.1007/s11084-016-9516-z
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      6
      Glycine Polymerization on Oxide Minerals
      Kitadai, Norio; Oonishi, Hiroyuki; Umemoto, Koichiro; Usui, Tomohiro; Fukushi, Keisuke; Nakashima, Satoru
      Origins of Life and Evolution of Biospheres (2017), 47 (2), 123-143CODEN: OLEBEM; ISSN:0169-6149. (Springer)
      It has long been suggested that mineral surfaces played an important role in peptide bond formation on the primitive Earth. However, it remains unclear which mineral species was key to the prebiotic processes. This is because great discrepancies exist among the reported catalytic efficiencies of minerals for amino acid polymns., owing to mutually different exptl. conditions. This study examd. polymn. of glycine (Gly) on nine oxide minerals (amorphous silica, quartz, α-alumina and γ-alumina, anatase, rutile, hematite, magnetite, and forsterite) using identical prepn., heating, and anal. procedures. Results showed that a rutile surface is the most effective site for Gly polymn. in terms of both amts. and lengths of Gly polymers synthesized. The catalytic efficiency decreased as rutile > anatase > γ-alumina > forsterite > α- alumina > magnetite > hematite > quartz > amorphous silica. Based on reported mol.-level information for adsorption of Gly on these minerals, polymn. activation was inferred to have arisen from deprotonation of the NH3+ group of adsorbed Gly to the nucleophilic NH2 group, and from withdrawal of electron d. from the carboxyl carbon to the surface metal ions. The orientation of adsorbed Gly on minerals is also a factor influencing the Gly reactivity. The examn. of Gly-mineral interactions under identical exptl. conditions has enabled the direct comparison of various minerals catalytic efficiencies and has made discussion of polymn. mechanisms and their relative influences possible Further systematic investigations using the approach reported herein (which are expected to be fruitful) combined with future microscopic surface analyses will elucidate the role of minerals in the process of abiotic peptide bond formation.
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    7. 7
      Eder, A. H.; Saetia, S.; Rode, B. M. HPLC and electrochemical investigations of the salt-induced peptide formation from glycine, alanine, valine and aspartic acid under possible prebiotic conditions. Inorg. Chim. Acta 1993, 207, 3– 10,  DOI: 10.1016/s0020-1693(00)91449-x
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      7
      HPLC and electrochemical investigations of the salt-induced peptide formation from glycine, alanine, valine and aspartic acid under possible prebiotic conditions
      Eder, Artur H.; Saetia, Somporn; Rode, Bernd M.
      Inorganica Chimica Acta (1993), 207 (1), 3-10CODEN: ICHAA3; ISSN:0020-1693.
      Peptide formation by the recently discovered salt-induced mechanism, the simplest possible prebiotic peptide generation process so far, has been studied with the example of some amino acids known to form by Miller or Fischer-Tropsch mechanisms in simulated primitive atm. expts. Valine and aspartic acid readily form peptides with glycine; self-condensation is obsd. for all acids except valine. Several findings give further indications toward the possible prebiotic relevance of the reaction: the obsd. preferential formation of peptide linkages, the shift from nature-irrelevant to nature-relevant peptide bonds in the presence of Cu(II) and the long conservation of optical purity in the reaction system. Addnl. data confirming the proposed reaction mechanism were obtained.
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    8. 8
      Flores, J. J.; Leckie, J. O. Peptide Formation Mediated by Cyanate. Nature 1973, 244, 435– 437,  DOI: 10.1038/244435a0
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      Peptide formation mediated by cyanate
      Flores, Jose J.; Leckie, James O.
      Nature (London, United Kingdom) (1973), 244 (5416), 435-7CODEN: NATUAS; ISSN:0028-0836.
      Peptide formation was enhanced by cyanate (I) added to hydroxylapatite or orthophosphates. When glycine is heated in the presence of hydroxylapatite or orthophosphates, diglycine (II) is formed. Addn. of inorg. I increased the yields of II, but its action as a condensing agent did not extend to all of the orthophosphates studied.
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    9. 9
      Huber, C.; Wächtershäuser, G. Peptides by Activation of Amino Acids with CO on (Ni,Fe)S Surfaces: Implications for the Origin of Life. Science 1998, 281, 670– 672,  DOI: 10.1126/science.281.5377.670
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      9
      Peptides by activation of amino acids with CO on (Ni,Fe)S surfaces: implications for the origin of life
      Huber, Claudia; Wachtershauser, Gunter
      Science (Washington, D. C.) (1998), 281 (5377), 670-674CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
      In expts. modeling volcanic or hydrothermal settings amino acids were converted into their peptides by use of copptd. (Ni,Fe)S and CO in conjunction with H2S (or CH3SH) as a catalyst and condensation agent at 100° and pH 7 to 10 under anaerobic, aq. conditions. These results demonstrate that amino acids can be activated under geochem. relevant conditions. They support a thermophilic origin of life and an early appearance of peptides in the evolution of a primordial metab.
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    10. 10
      Lambert, J.-F. Adsorption and Polymerization of Amino Acids on Mineral Surfaces: A Review. Origins Life Evol. Biospheres 2008, 38, 211– 242,  DOI: 10.1007/s11084-008-9128-3
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      10
      Adsorption and Polymerization of Amino Acids on Mineral Surfaces: A Review
      Lambert, Jean-Francois
      Origins of Life and Evolution of Biospheres (2008), 38 (3), 211-242CODEN: OLEBEM; ISSN:0169-6149. (Springer)
      A review. The present paper offers a review of recent (post-1980) work on amino acid adsorption and thermal reactivity on oxide and sulfide minerals. It is performed in the general frame of evaluating Bernal's hypothesis of prebiotic polymn. in the adsorbed state, but written from a surface scientist's point of view. After a general discussion of the thermodn. of the problem and exactly what effects surfaces should have to make adsorbed-state polymn. a viable scenario, we examine some practical difficulties in exptl. design and their bearing on the conclusions that can be drawn from extant works, including the relevance of the various available characterization techniques. We then present the state of the art concerning the mechanisms of the interactions of amino acids with mineral surfaces, including results from prebiotic chem.-oriented studies, but also from several different fields of application, and discuss the likely consequences for adsorption selectivities. Finally, we briefly summarize the data concerning thermally activated amide bond formation of adsorbed amino acids without activating agents. The reality of the phenomenon is established beyond any doubt, but our understanding of its mechanism and therefore of its prebiotic potential is very fragmentary. The review concludes with a discussion of future work needed to fill the most conspicuous gaps in our knowledge of amino acids/mineral surfaces systems and their reactivity.
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    11. 11
      Kumar, A.; Kamaluddin Oligomerization of glycine and alanine on metal(II) octacynaomolybdate(IV): role of double metal cyanides in prebiotic chemistry. Amino Acids 2012, 43, 2417– 2429,  DOI: 10.1007/s00726-012-1320-0
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      11
      Oligomerization of glycine and alanine on metal(II) octacynaomolybdate(IV): role of double metal cyanides in prebiotic chemistry
      Kumar, Anand; Kamaluddin
      Amino Acids (2012), 43 (6), 2417-2429CODEN: AACIE6; ISSN:0939-4451. (SpringerWienNewYork)
      Condensation reactions of amino acid (glycine and alanine) on the surface of metal(II) octacyanomolybdate(IV) (MOCMo) complexes are investigated using high-performance liq. chromatog. (HPLC) and electron spray ionizations-mass spectroscopy (ESI-MS). The series of MOCMo have been synthesized and the effect of outer sphere metal ions present in the MOCMo on the oligomerization of glycine and alanine at different temp. and time found out. Formation of peptides was obsd. to start after 7 days at 60 °C. Maximum yield of peptides was found after 35 days at 90 °C. It has been found that zinc(II) octacyanomolybdate(IV) and cobalt(II) were the most effective metal cations present in outer sphere of the MOCMo for the prodn. of high yield of oligomerized products. Surface area of MOCMo seems to play dominating parameter for the oligomerization of alanine and glycine. The results of the present study reveal the role of MOCMo in chem. evolution for the oligomerization of biomols.
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    12. 12
      Sakata, K.; Yabuta, H.; Kondo, T. Effects of metal ions and pH on the formation and decomposition rates of di- and tri-peptides in aqueous solution. Geochem. J. 2014, 48, 219– 230,  DOI: 10.2343/geochemj.2.0300
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      12
      Effects of metal ions and pH on the formation and decomposition rates of di- and tri-peptides in aqueous solution
      Sakata, Kasumi; Yabuta, Hikaru; Kondo, Tadashi
      Geochemical Journal (2014), 48 (2), 219-230CODEN: GEJOBE; ISSN:0016-7002. (Terra Scientific Publishing Co.)
      The recent discovery of active deep-sea hydrothermal systems venting high-pH fluids suggests that the prebiotic chem. of the hydrothermal systems of early earth may have been more diverse than previously thought. To det. the most favorable conditions for prebiotic oligomerization, the effects of metal ions (Ca2+, Mg2+, Zn2+, Fe2+, Mn2+, and Cu2+) and pH on the formation and decompn. rates of glycylglycine (GlyGly), glycylglycylglycine (GlyGlyGly), and diketopiperazine (DKP) in aq. soln. were investigated. Glycine (Gly) solns. contg. metal ions were heated for 1-74 days at 140°C under various pH conditions and the samples were analyzed by high-performance liq. chromatog. GlyGly and DKP were produced in all samples regardless of the presence or absence of metal ions. GlyGly yields were higher under basic conditions (pH 9.8-9.9) than under acidic or neutral conditions. Moreover, GlyGly yields in the presence of Cu2+ and Zn2+ were higher than in the absence of Cu2+ and Zn2+; in the presence of metal ions other than Cu2+ and Zn2+, GlyGly yields were lower. The dimerization rate const. of Gly (k1) increased in the presence of Cu2+. GlyGlyGly was only produced in samples with Cu2+ and the yield was 5 times higher under basic conditions (pH 9.8) than under acidic (pH 3.4) or neutral (pH 7.1) conditions. However, other metal ions inhibited prebiotic peptide synthesis by catalyzing hydrolysis or chelation with amino acids. These results reflect the high stability of Cu2+ complexes with amino acids or peptides in the salt-induced peptide formation reaction, particularly at high pH. Although elongation of oligopeptides was not favored, formation of metal-amino acid or metal-short peptide chelates may have facilitated primitive biol. functions and expanded prebiotic reaction fields because of their mobility in the earth's early oceans.
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    13. 13
      Dalai, P.; Pleyer, H. L.; Strasdeit, H.; Fox, S. The Influence of Mineral Matrices on the Thermal Behavior of Glycine. Origins Life Evol. Biospheres 2017, 47, 427– 452,  DOI: 10.1007/s11084-016-9523-0
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      13
      The Influence of Mineral Matrices on the Thermal Behavior of Glycine
      Dalai, Punam; Pleyer, Hannes Lukas; Strasdeit, Henry; Fox, Stefan
      Origins of Life and Evolution of Biospheres (2017), 47 (4), 427-452CODEN: OLEBEM; ISSN:0169-6149. (Springer)
      On the Hadean-Early Archean Earth, the first islands must have provided hot and dry environments for abiotically formed org. mols. The heat sources, mainly volcanism and meteorite impacts, were also available on Mars during the Noachian period. In recent work simulating this scenario, we have shown that neat glycine forms a black, sparingly water-sol. polymer ("thermomelanoid") when dry-heated at 200 °C under pure nitrogen. The present study explores whether relevant minerals and mineral mixts. can change this thermal behavior. Most expts. were conducted at 200 or 250 °C for 2 or 7 days. The mineral matrixes used were phyllosilicates (Ca-montmorillonites SAz-1 and STx-1, Na-montmorillonite SAz-1-Na, nontronite NAu-1, kaolinite KGa-1), salts (NaCl, NaCl-KCl, CaCl2, artificial sea salt, gypsum, magnesite), picritic basalt, and three Martian regolith simulants (P-MRS, S-MRS, JSC Mars-1A). The main anal. method employed was high-performance liq. chromatog. (HPLC). Glycine intercalated in SAz-1 and SAz-1-Na was well protected against thermomelanoid formation and sublimation at 200 °C: after 2 days, 95 and 79 %, resp., had either survived unaltered or been transformed into the cyclic dipeptide (DKP) and linear peptides up to Gly6. The glycine survival rate followed the order SAz-1 > SAz-1-Na > STx-1 ≈ NAu-1 > KGa-1. Very good protection was also provided by artificial sea salt (84 % unaltered glycine after 200 °C for 7 days). P-MRS promoted the condensation up to Gly6, consistent with its high phyllosilicate content. The remaining matrixes were less effective in preserving glycine as such or as peptides.
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    14. 14
      Porter, T. L.; Eastman, M. P.; Hagerman, M. E.; Price, L. B.; Shand, R. F. Site-specific Prebiotic Oligomerization Rreactions of Glycine on the Surface of Hectorite. J. Mol. Evol. 1998, 47, 373– 377,  DOI: 10.1007/pl00006394
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      14
      Site-specific prebiotic oligomerization reactions of glycine on the surface of hectorite
      Porter, Timothy L.; Eastman, Michael P.; Hagerman, Michael E.; Price, Lance B.; Shand, Richard F.
      Journal of Molecular Evolution (1998), 47 (4), 373-377CODEN: JMEVAU; ISSN:0022-2844. (Springer-Verlag New York Inc.)
      Condensation reactions of the amino acid glycine on the surface of Cu(II)-exchanged hectorite are investigated using the technique of scanning force microscopy. Prebiotic conditions are simulated using alternate wetting and heating cycles. Concn., immobilization, and subsequent polymn. resulting in glycine oligomers are seen to occur primarily at step edges or faults in the topmost layer. Condensation reactions also occur within tiny micropores or defects in the topmost layer. These reactions are facilitated by the availability of intergallery metal cations at the step edges or pores in the surface region.
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      Porter, T. L.; Eastman, M. P.; Bain, E.; Begay, S. Analysis of peptides synthesized in the presence of SAz-1 montmorillonite and Cu2+ exchanged hectorite. Biophys. Chem. 2001, 91, 115– 124,  DOI: 10.1016/s0301-4622(01)00159-4
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      15
      Analysis of peptides synthesized in the presence of SAz-1 montmorillonite and Cu2+ exchanged hectorite
      Porter, T. L.; Eastman, M. P.; Bain, E.; Begay, S.
      Biophysical Chemistry (2001), 91 (2), 115-124CODEN: BICIAZ; ISSN:0301-4622. (Elsevier Science B.V.)
      We have investigated the synthesis of oligopeptides contg. glycine and tyrosine in the presence of the clay minerals montmorillonite (non-exchanged, SAz-1) and Cu2+ exchanged hectorite. In both cases, homopolymers of the two amino acids are formed, as are mixed peptides. In the case of Cu2+ hectorite, mixed oligopeptides up to trimers are detected in small amts. For montmorillonite, heterogeneous oligopeptides up to hexamers are detected. Our expts. indicate montmorillonite is more effective in promoting oligopeptide formation than Cu2+ hectorite. Anal. of the oligopeptide sequences formed on the montmorillonite surfaces indicates preferential synthesis of certain Gly-Tyr sequences over others.
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      Imai, E.; Honda, H.; Hatori, K.; Brack, A.; Matsuno, K. Elongation of Oligopeptides in a Simulated Submarine Hydrothermal System. Science 1999, 283, 831– 833,  DOI: 10.1126/science.283.5403.831
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      16
      Elongation of oligopeptides in a simulated submarine hydrothermal system
      Imai, Ei-ichi; Honda, Hajime; Hatori, Kuniyuki; Brack, Andre; Matsuno, Koichiro
      Science (Washington, D. C.) (1999), 283 (5403), 831-833CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
      Oligomerization of a peptide was attempted in a flow reactor that simulated a submarine hydrothermal system. When fluid contg. glycine repeatedly circulated through the hot and cold regions in the reactor, oligopeptides were made from glycine. When divalent ions (such as copper ions) were added under acidic conditions, oligoglycine was elongated up to hexaglycine. This observation suggests that prebiotic monomers could have oligomerized in the vicinity of submarine hydrothermal vents on primitive Earth.
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      Paecht-Horowitz, M.; Berger, J.; Katchalsky, A. Prebiotic Synthesis of Polypeptides by Heterogeneous Polycondensation of Amino-acid Adenylates. Nature 1970, 228, 636– 639,  DOI: 10.1038/228636a0
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      17
      Prebiotic synthesis of polypeptides by heterogeneous polycondensation of amino acid adenylates
      Paecht-Horowitz, M.; Berger, J.; Katchalsky, Aharon
      Nature (London, United Kingdom) (1970), 228 (5272), 636-9CODEN: NATUAS; ISSN:0028-0836.
      Alanyl adenylate underwent heterogeneous polymn. in the presence of montmorillonite of particle size 700 Å. The yield from 1 g alanyl adenylate in 24 hr was 10.3 mg peptide d.p. 9, 35.2 mg peptide d.p. 16, and 20 mg peptide d.p. 27. Many peptide units contained a terminal adenylic acid group as an ester between the amino acid and the adenylic OH. Alk. medium was necessary to dissoc. ammonium groups for polymn. to occur. Liberated adenylic acid was neutralized with NaOH. Illite similarly yielded peptides of d.p. 10-16.
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      Bujdák, J.; Le Son, H.; Rode, B. M. Montmorillonite Catalyzed Peptide Bond Formation: The Effect of Exchangeable Cations. J. Inorg. Biochem. 1996, 63, 119– 124,  DOI: 10.1016/0162-0134(95)00186-7
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      18
      Montmorillonite catalyzed peptide bond formation: the effect of exchangeable cations
      Bujdak, Juraj; Son, Hoang Le; Rode, Bernd Michael
      Journal of Inorganic Biochemistry (1996), 63 (2), 119-124CODEN: JIBIDJ; ISSN:0162-0134. (Elsevier)
      The effect of exchangeable cations, namely, alkali and alk. metal, ammonium and aluminum ions, on montmorillonite (M) catalyzed peptide formation was investigated. Amino acid dimerization and peptide chain elongation proceed with relatively low yields on macroscopically swelling montmorillonites (Li-M, Na-M) due to redistribution and insufficient concn. of reactant mols. on the clay surface. Cyclic anhydride (CA) formation, proceeding by monomol. mechanism, is primarily affected by the accessibility of catalytic sites for dimer activation. Weaker sorbed exchangeable cations do not block catalytic sites, and thus favor CA formation.
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      Fuchida, S.; Masuda, H.; Shinoda, K. Peptide Formation Mechanism on Montmorillonite Under Thermal Conditions. Origins Life Evol. Biospheres 2014, 44, 13– 28,  DOI: 10.1007/s11084-014-9359-4
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      19
      Peptide Formation Mechanism on Montmorillonite Under Thermal Conditions
      Fuchida, Shigeshi; Masuda, Harue; Shinoda, Keiji
      Origins of Life and Evolution of Biospheres (2014), 44 (1), 13-28CODEN: OLEBEM; ISSN:0169-6149. (Springer)
      The oligomerization of amino acids is an essential process in the chem. evolution of proteins, which are precursors to life on Earth. Although some researchers have obsd. peptide formation on clay mineral surfaces, the mechanism of peptide bond formation on the clay mineral surface has not been clarified. In this study, the thermal behavior of glycine (Gly) adsorbed on montmorillonite was obsd. during heating expts. conducted at 150 °C for 336 h under dry, wet, and dry-wet conditions to clarify the mechanism. Approx. 13.9 % of the Gly monomers became peptides on montmorillonite under dry conditions, with diketopiperazine (cyclic dimer) being the main product. On the other hand, peptides were not synthesized in the absence of montmorillonite. Results of IR anal. showed that the Gly monomer was mainly adsorbed via hydrogen bonding between the pos. charged amino groups and neg. charged surface sites (i.e., Lewis base sites) on the montmorillonite surface, indicating that the Lewis base site acts as a catalyst for peptide formation. In contrast, peptides were not detected on montmorillonite heated under wet conditions, since excess water shifted the equil. towards hydrolysis of the peptides. The presence of water is likely to control thermodn. peptide prodn., and clay minerals, esp. those with electrophilic defect sites, seem to act as a kinetic catalyst for the peptide formation reaction.
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    20. 20
      Shanker, U.; Bhushan, B.; Bhattacharjee, G.; Kamaluddin Oligomerization of Glycine and Alanine Catalyzed by Iron Oxides: Implications for Prebiotic Chemistry. Origins Life Evol. Biospheres 2012, 42, 31– 45,  DOI: 10.1007/s11084-012-9266-5
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      20
      Oligomerization of Glycine and Alanine Catalyzed by Iron Oxides: Implications for Prebiotic Chemistry
      Shanker, Uma; Bhushan, Brij; Bhattacharjee, G.; Kamaluddin
      Origins of Life and Evolution of Biospheres (2012), 42 (1), 31-45CODEN: OLEBEM; ISSN:0169-6149. (Springer)
      Iron oxide minerals are probable constituents of the sediments present in geothermal regions of the primitive earth. They might have adsorbed different org. monomers (amino acids, nucleotides etc.) and catalyzed polymn. processes leading to the formation of the first living cell. In the present work we tested the catalytic activity of three forms of iron oxides (Goethite, Akaganeite and Hematite) in the intermol. condensation of each of the amino acids glycine and L-alanine. The effect of zinc oxide and titanium dioxide on the oligomerization has also been studied. Oligomerization studies were performed for 35 days at three different temps. 50, 90 and 120°C without applying drying/wetting cycling. The products formed were characterized by HPLC and ESI-MS techniques. All three forms of iron oxides catalyzed peptide bond formation (23.2% of gly2 and 10.65% of ala2). The reaction was monitored every 7 days. Formation of peptides was obsd. to start after 7 days at 50°C. Maximum yield of peptides was found after 35 days at 90°C. Reaction at 120°C favors formation of diketopiperazine derivs. It is also important to note that after 35 days of reaction, goethite produced dimer and trimer with the highest yield among the oxides tested. We suggest that the activity of goethite could probably be due to its high surface area and surface acidity.
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      Rode, B. M.; Schwendinger, M. G. Copper-Catalyzed Amino Acid Condensation in Water—A Simple Possible Way of Prebiotic Peptide Formation. Origins Life Evol. Biospheres 1990, 20, 401– 410,  DOI: 10.1007/bf01808134
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      Bhushan, B.; Nayak, A.; Kamaluddin Role of manganese oxides in peptide synthesis: implication in chemical evolution. Int. J. Astrobiol. 2017, 16, 360– 367,  DOI: 10.1017/s1473550416000471
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      Role of manganese oxides in peptide synthesis: implication in chemical evolution
      Bhushan, Brij; Nayak, Arunima; Kamaluddin
      International Journal of Astrobiology (2017), 16 (4), 360-367CODEN: IJANFR; ISSN:1473-5504. (Cambridge University Press)
      During the course of chem. evolution the role of metal oxides may have been very significant in catalyzing the polymn. of biomonomers. The peptide bond formation of alanine (ala) and glycine (gly) in the presence of various oxides of manganese were performed for a period of 35 days at three different temps. 50, 90 and 120°C without applying drying/wetting cycling. The reaction was monitored every week. The products formed were characterized by high-performance liq. chromatog. and electrospray ionization-mass spectrometry techniques. Trace amt. of oligomers was obsd. at 50°C. Maximum yield of peptides was found after 35 days at 90°C. It is important to note that very high temps. of 120°C favored the formation of diketopiperazine derivs. Different types of manganese oxides [manganosite (MnO), bixbyite (Mn2O3), hausmannite (Mn3O4) and pyrolusite (MnO2)] were used as catalyst. The MnO catalyzed glycine to cyclic (Gly)2, (Gly)2 and (Gly)3, and alanine, to cyclic (Ala)2 and (Ala)2. Mn3O4 also produced the same products but in lesser yield, while Mn2O3 and MnO2 produced cyclic anhydride of glycine and alanine with a trace amt. of dimers and trimmers. Manganese of lower oxidn. state is much more efficient in propagating the reaction than higher oxidn. states. The possible mechanism of these reactions and the relevance of the results for the prebiotic chem. are discussed.
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      Beaufils, D.; Jepaul, S.; Liu, Z.; Boiteau, L.; Pascal, R. The Activation of Free Dipeptides Promoted by Strong Activating Agents in Water Does not Yield Diketopiperazines. Origins Life Evol. Biospheres 2016, 46, 19– 30,  DOI: 10.1007/s11084-015-9455-0
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      The Activation of Free Dipeptides Promoted by Strong Activating Agents in Water Does not Yield Diketopiperazines
      Beaufils, Damien; Jepaul, Sandra; Liu, Ziwei; Boiteau, Laurent; Pascal, Robert
      Origins of Life and Evolution of Biospheres (2016), 46 (1), 19-30CODEN: OLEBEM; ISSN:0169-6149. (Springer)
      The activation of dipeptides was studied in the perspective of the abiotic formation of oligopeptides of significant length as a requirement for secondary structure formation. The formation of piperazin-2,5-diones (DKP), previously considered as a dead end when activating free dipeptides, was shown in this work to be efficiently suppressed when using strong activating agents (e.g., carbodiimides). This behavior was explained by the fast formation of a 5(4H)-oxazolone intermediate at a rate that exceeds the time scale of the rotation of the peptide bond from the predominant trans-conformation into the cis-isomer required for DKP formation. No DKP was obsd. when using strong activating agents whereas phosphate mixed anhydrides or moderately activated esters were obsd. to predominantly yield DKP. The DKP side-reaction no longer constitutes a drawback for the C-terminus elongation of peptides. These results are considered as addnl. evidence that pathways involving strong activation are required to drive the emergence of living entities rather than close to equil. processes.
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      Ehler, K. W.; Orgel, L. E. N,N′-Carbonyldiimidazole-Induced Peptide Formation in Aqueous Solution. Biochim. Biophys. Acta, Protein Struct. 1976, 434, 233– 243,  DOI: 10.1016/0005-2795(76)90055-6
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      24
      N,N'-carbonyldiimidazole-induced peptide formation in aqueous solution
      Ehler, K. W.; Orgel, L. E.
      Biochimica et Biophysica Acta, Protein Structure (1976), 434 (1), 233-43CODEN: BBPTBH; ISSN:0005-2795.
      N,N'-carbonyldiimidazole reacts with glycine in aq. imidazole buffers at 0° to yield N-[1-imidazolylcarbonyl]glycine, which condenses slowly to give oligopeptides.
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      Danger, G.; Boiteau, L.; Cottet, H.; Pascal, R. The Peptide Formation Mediated by Cyanate Revisited. N-Carboxyanhydrides as Accessible Intermediates in the Decomposition of N-Carbamoylamino Acids. J. Am. Chem. Soc. 2006, 128, 7412– 7413,  DOI: 10.1021/ja061339+
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      The Peptide Formation Mediated by Cyanate Revisited. N-Carboxyanhydrides as Accessible Intermediates in the Decomposition of N-Carbamoylamino Acids
      Danger, Gregoire; Boiteau, Laurent; Cottet, Herve; Pascal, Robert
      Journal of the American Chemical Society (2006), 128 (23), 7412-7413CODEN: JACSAT; ISSN:0002-7863. (American Chemical Society)
      Similar to many ureas, N-carbamoylamino acids were shown to be hydrolyzed in aq. soln. through elimination mechanisms at close to neutral pH, the nucleophilic attack of water being a minor process. Two competing elimination mechanisms can take place involving either cyanate or isocyanate transient intermediates. Peptide formation was obsd. and attributed to the latter pathway through the intermediacy of amino acid N-carboxyanhydride (NCA). Eventually, cyanate and its precursors (including urea) unexpectedly behave as amino acid activating agents because of their ability in amino acid carbamoylation. Owing to its ability to generate a background prebiotic prodn. of NCAs on the primitive Earth, this reaction is suggested to have contributed to the origin of life process.
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      Leman, L.; Orgel, L.; Ghadiri, M. R. Carbonyl Sulfide-Mediated Prebiotic Formation of Peptides. Science 2004, 306, 283– 286,  DOI: 10.1126/science.1102722
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      Carbonyl Sulfide-Mediated Prebiotic Formation of Peptides
      Leman, Luke; Orgel, Leslie; Ghadiri, M. Reza
      Science (Washington, DC, United States) (2004), 306 (5694), 283-286CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
      Almost all discussions of prebiotic chem. assume that amino acids, nucleotides, and possibly other monomers were first formed on the Earth or brought to it in comets and meteorites, and then condensed nonenzymically to form oligomeric products. However, attempts to demonstrate plausibly prebiotic polymn. reactions have met with limited success. We show that carbonyl sulfide (COS), a simple volcanic gas, brings about the formation of peptides from amino acids under mild conditions in aq. soln. Depending on the reaction conditions and additives used, exposure of α-amino acids to COS generates peptides in yields of up to 80% in minutes to hours at room temp.
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      Kawamura, K.; Takeya, H.; Kushibe, T. Effect of condensation agents and minerals for oligopeptide formation under mild and hydrothermal conditions in related to chemical evolution of proteins. Adv. Space Res. 2009, 44, 267– 275,  DOI: 10.1016/j.asr.2009.03.027
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      Effect of condensation agents and minerals for oligopeptide formation under mild and hydrothermal conditions in related to chemical evolution of proteins
      Kawamura, Kunio; Takeya, Hitoshi; Kushibe, Takao
      Advances in Space Research (2009), 44 (2), 267-275CODEN: ASRSDW; ISSN:0273-1177. (Elsevier Ltd.)
      The role of condensation agents and minerals for oligopeptide formation was inspected to see whether minerals possess catalytic activity under mild and hydrothermal conditions. Under mild conditions, oligopeptide formation from neg. charged amino acids (Asp and Glu) using different minerals and the elongation of alanine oligopeptides ((Ala)2-(Ala)5) were attempted using apatite minerals. Oligo(Asp) up to 10 amino acid units from Asp were obsd. in the presence of 1-ethyl-3-(3)-dimethylaminopropyl carbodiimide (EDC). Notable influence of minerals was not detected for the oligo(Asp) formation. Oligo(Asp) was gradually degraded by the further incubation in the presence of EDC in both the absence and presence of minerals. The formation of oligo(Glu) was less efficient in the presence of carbonyldiimidazole. The elongation from (Ala)3, (Ala)4, and (Ala)5 and the formation of diketopiperazine from (Ala)2 proceeded immediately in the presence of EDC in the meantime of the sample prepns. In addn., it was unexpected that the disappearance of the products and the reformation of the reactants occurred by the further incubation for 24 h; for instance, (Ala)5 decreased but (Ala)4 increased with increasing the reaction time in the reaction of (Ala)4 with EDC. These facts suggest that the activation of the reactant amino acids or peptides immediately occurs. Under the simulated hydrothermal conditions, EDC did not enhance the formation of oligopeptides from Asp, Glu or Ala nor the spontaneous formation of (Ala)5 from (Ala)4.
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      Forsythe, J. G.; Yu, S.-S.; Mamajanov, I.; Grover, M. A.; Krishnamurthy, R.; Fernández, F. M.; Hud, N. V. Ester-Mediated Amide Bond Formation Driven by Wet-Dry Cycles: A Possible Path to Polypeptides on the Prebiotic Earth. Angew. Chem., Int. Ed. 2015, 54, 9871– 9875,  DOI: 10.1002/anie.201503792
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      Ester-Mediated Amide Bond Formation Driven by Wet-Dry Cycles: A Possible Path to Polypeptides on the Prebiotic Earth
      Forsythe, Jay G.; Yu, Sheng-Sheng; Mamajanov, Irena; Grover, Martha A.; Krishnamurthy, Ramanarayanan; Fernandez, Facundo M.; Hud, Nicholas V.
      Angewandte Chemie, International Edition (2015), 54 (34), 9871-9875CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Although it is generally accepted that amino acids were present on the prebiotic earth, the mechanism by which α-amino acids were condensed into polypeptides before the emergence of enzymes remains unsolved. Here, we demonstrate a prebiotically plausible mechanism for peptide (amide) bond formation that is enabled by α-hydroxy acids, which were likely present along with amino acids on the early earth. Together, α-hydroxy acids and α-amino acids form depsipeptides - oligomers with a combination of ester and amide linkages - in model prebiotic reactions that are driven by wet-cool/dry-hot cycles. Through a combination of ester-amide bond exchange and ester bond hydrolysis, depsipeptides are enriched with amino acids over time. These results support a long-standing hypothesis that peptides might have arisen from ester-based precursors.
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      A novel synthesis of polypeptides
      Oro, J.; Guidry, C. L.
      Nature (London, United Kingdom) (1960), 186 (), 156-7CODEN: NATUAS; ISSN:0028-0836.
      The product, obtained by heating glycinamide or glycinamide-HCl and NH4OH at 100° 20 hrs. in a closed vessel, was dialyzed until no low-mol.-wt. compds. remained and then lyophilized. The degree of polymerization was detd. by either the Sorensen formol titration in LiBr or a modified Van Slyke amino-N method (cf. CA 38, 5145). Pure cryst. glycinamide was 34% polymerized and gave a 75 mole-% yield of polymer, tannish white powder, insol. in H2O, sol. in concd; aq. LiBr, pos. biuret test, yielded only glycine on acid hydrolysis. Kinetic study showed that the initial reaction rate was sufficiently fast to be able to compete with side reactions. Data for the proof of the polyglycine structure by infrared spectra was given.
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      Nagayama, M.; Takaoka, O.; Inomata, K.; Yamagata, Y. Diketopiperazine-Mediated Peptide Formation in Aqueous Solution. Origins Life Evol. Biospheres 1990, 20, 249– 257,  DOI: 10.1007/bf01808107
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      Diketopiperazine-mediated peptide formation in aqueous solution
      Nagayama, M.; Takaoka, O.; Inomata, K.; Yamagata, Y.
      Origins of Life and Evolution of the Biosphere (1990), 20 (3-4), 249-57CODEN: OLEBEM; ISSN:0169-6149.
      Though diketopiperazines (DKP) are formed in most exptl. studies on prebiotic peptide formation, the mols. have not been considered in the studies of chem. evolution. Triglycine, tetraglycine, or pentaglycine are formed in an aq. soln. of glycine anhydride (a DKP)and glycine, diglycine, or triglycine, resp. A reaction of alanine with DKP resulted in the formation of glycylglycylalanine under the same conditions. The formation of the peptide bonds proceeds through the nucleophilic attack of an amino group of the amino acids or the oligoglycines on the DKP accompanied by ring-opening. The formation of glycine anhydride, di-, tri-, and tetraglycines was also obsd. in a mixed aq. soln. of urea and glycine in an open system to allow the evapn. of ammonia. A probable pathway is proposed for prebiotic peptide formation through diketopiperazine on the primitive Earth.
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      Takaoka, O.; Yamagata, Y.; Inomata, K. Diketopiperazine-Mediated Peptide Formation in Aqueous Solution II. Catalytic Effect of Phosphate. Origins Life Evol. Biospheres 1991, 21, 113– 118,  DOI: 10.1007/bf01809440
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      Diketopiperazine-mediated peptide formation in aqueous solution. II. Catalytic effect of phosphate
      Takaoka, O.; Yamagata, Y.; Inomata, K.
      Origins of Life and Evolution of the Biosphere (1991), 21 (3), 113-18CODEN: OLEBEM; ISSN:0169-6149.
      Phosphate catalyzed the condensation of diketopiperazine (DITP) with glycine (Gly) or oligoglycines (Glyn) to produce longer oligoglycines (Glyn+2). Formation of Gly4 from DKP (0.1 M) and Gly2 (0.1 M) in phosphate soln. of various concns. was investigated at a neutral pH at 41°. The yields of Gly4 increased almost linearly with the concn. of phosphate from 0.06 M to 0.24 M. The yield in 0.24 M phosphate soln. was approx. one hundred times as high as that in the absence of the phosphate, whereas in the case of Gly3 formation from DKP and Gly the effect of the phosphate was of ten times lower than in the former case. Orthophosphate was the most effective catalyst among the various kind of chems. tried in the present investigation including polyphosphates.
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      Lahav, N.; White, D.; Chang, S. Peptide Formation in the Prebiotic Era: Thermal Condensation of Glycine in Fluctuating Clay Environments. Science 1978, 201, 67– 69,  DOI: 10.1126/science.663639
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      Peptide formation in the prebiotic era: thermal condensation of glycine in fluctuating clay environments
      Lahav N; White D; Chang S
      Science (New York, N.Y.) (1978), 201 (4350), 67-9 ISSN:0036-8075.
      As geologically relevant models of prebiotic environments, systems consisting of clay, water, and amino acids were subjected to cyclic variations in temperature and water content. Fluctuations of both variables produced longer oligopeptides in higher yields than were produced by temperature fluctuations alone. The results suggest that fluctuating environments provided a favorable geological setting in which the rate and extent of chemical evolution would have been determined by the number and frequency of cycles.
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      Rohlfing, D. L. Thermal Polyamino Acids: Synthesis at Less Than 100 °C. Science 1976, 193, 68– 70,  DOI: 10.1126/science.935858
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      Thermal poly(amino acids): synthesis at less than 100°C
      Rohlfing, Duane L.
      Science (Washington, DC, United States) (1976), 193 (4247), 68-70CODEN: SCIEAS; ISSN:0036-8075.
      Thermally prepd. polyamino acids, regarded as models for prebiotic protein, typically have been synthesized at 120°-200°. In this study, 3 different sets of amino acid mixts. yielded material of relatively high-mol. wt. (mol. sieving and diffusion techniques) when heated for ≤81 days at 85°, 75°, and 65°. These temps., which today are generated by radiation from the sun in some terrestrial locales, probably were more common on the prebiotic earth than those above the b.p. of H2O. The results suggest that prebiotic polyamino acids were relatively common and widespread.
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      Rodriguez-Garcia, M.; Surman, A. J.; Cooper, G. J.; Suárez-Marina, I.; Hosni, Z.; Lee, M. P.; Cronin, L. Formation of oligopeptides in high yield under simple programmable conditions. Nat. Commun. 2015, 6, 8385,  DOI: 10.1038/ncomms9385
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      Formation of oligopeptides in high yield under simple programmable conditions
      Rodriguez-Garcia, Marc; Surman, Andrew J.; Cooper, Geoffrey J. T.; Suarez-Marina, Irene; Hosni, Zied; Lee, Michael P.; Cronin, Leroy
      Nature Communications (2015), 6 (), 8385CODEN: NCAOBW; ISSN:2041-1723. (Nature Publishing Group)
      Many high-yielding reactions for forming peptide bonds have been developed but these are complex, requiring activated amino-acid precursors and heterogeneous supports. Herein we demonstrate the programmable one-pot dehydration-hydration condensation of amino acids forming oligopeptide chains in around 50% yield. A digital recursive reactor system was developed to investigate this process, performing these reactions with control over parameters such as temp., no. of cycles, cycle duration, initial monomer concn. and initial pH. Glycine oligopeptides up to 20 amino acids long were formed with very high monomer-to-oligomer conversion, and the majority of these products comprised three amino acid residues or more. Having established the formation of glycine homo-oligopeptides, we then demonstrated the co-condensation of glycine with eight other amino acids (Ala, Asp, Glu, His, Lys, Pro, Thr and Val), incorporating a range of side-chain functionality.
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      Fujimoto, C.; Shinozaki, A.; Mimura, K.; Nishida, T.; Gotou, H.; Komatsu, K.; Kagi, H. Pressure-induced oligomerization of alanine at 25 °C. Chem. Commun. 2015, 51, 13358– 13361,  DOI: 10.1039/c5cc03665h
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      Pressure-induced oligomerization of alanine at 25°C
      Fujimoto, Chikako; Shinozaki, Ayako; Mimura, Koichi; Nishida, Tamihito; Gotou, Hirotada; Komatsu, Kazuki; Kagi, Hiroyuki
      Chemical Communications (Cambridge, United Kingdom) (2015), 51 (69), 13358-13361CODEN: CHCOFS; ISSN:1359-7345. (Royal Society of Chemistry)
      Pressure-induced oligomerization was found from high-pressure expts. at 25° on alanine powder soaked in its satd. aq. soln. The oligomerization to alanylalanine occurred at 5 GPa. The max. yields of alanylalanine and trialanine were, resp., 1.1 × 10-3 and 1.3 × 10-4 at 11 GPa.
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      Sugahara, H.; Mimura, K. Glycine oligomerization up to triglycine by shock experiments simulating comet impacts. Geochem. J. 2014, 48, 51– 62,  DOI: 10.2343/geochemj.2.0285
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      Glycine oligomerization up to triglycine by shock experiments simulating comet impacts
      Sugahara, Haruna; Mimura, Koichi
      Geochemical Journal (2014), 48 (1), 51-62CODEN: GEJOBE; ISSN:0016-7002. (Terra Scientific Publishing Co.)
      We conducted shock expts. simulating comet impacts to assess the feasibility of peptide synthesis by such a process. We used frozen mixt. of the amino acid glycine, water ice, and silicate (forsterite) as the starting material and applied impact shocks ranging from 4.8 to 26.3 GPa using a vertical propellant gun under cryogenic conditions (77 K). The results show that amino acid oligomerization up to trimers can be achieved. Further, linear peptides (dipeptide and tripeptide forms), which are important materials for the further elongation of peptide chains, were obtained in yields of one or two magnitudes greater than that of cyclic peptide form (diketopiperazine). These results contrast with those by Blank et al. (2001) for shock expts. of amino acid solns. at room temp., which showed the synthesis of a comparable amt. of diketopiperazines to that of the linear peptides. Thus, the existence of cryogenic conditions at the point of impact shock may be crit. for the formation of linear peptides. Our results demonstrate that comet impacts could have supplied a significant amt. of linear peptides on the early Earth and other extraterrestrial bodies.
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      Simakov, M. B.; Kuzicheva, E. A.; Mal’ko, I. L.; Dodonova, N. Y. Abiogenic synthesis of oligopeptides in solid state under action of vacuum ultraviolet light (100-200 nm). Adv. Space Res. 1996, 18, 61– 64,  DOI: 10.1016/0273-1177(96)00028-2
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      Abiogenic synthesis of oligopeptides in solid state under action of vacuum ultraviolet light (100-200 NM)
      Simakov, M. B.; Kuzicheva, E. A.; Mal'ko, I. L.; Dodonova, N. Ya.
      Advances in Space Research (1996), 18 (12, Life Sciences: Space and Mars Recent Results), 61-64CODEN: ASRSDW; ISSN:0273-1177. (Elsevier)
      Thin films contg. a mixt. of aliph. (glycine) and arom. (tryptophan or tyrosine) amino acids were exposed to vacuum UV radiation (VUV) with wavelengths 100-200 nm. Dipeptides (glycyltryptophan and glycyltyrosine) were synthesized under these conditions. The use of VUV and γ-radiation were compared. Polymn. is an essential step in prebiol. evolution and we have shown that this stage probably occurred during an early solar system period.
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      Otake, T.; Taniguchi, T.; Furukawa, Y.; Kawamura, F.; Nakazawa, H.; Kakegawa, T. Stability of Amino Acids and Their Oligomerization Under High-Pressure Conditions: Implications for Prebiotic Chemistry. Astrobiology 2011, 11, 799– 813,  DOI: 10.1089/ast.2011.0637
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      38
      Stability of Amino Acids and Their Oligomerization Under High-Pressure Conditions: Implications for Prebiotic Chemistry
      Otake, Tsubasa; Taniguchi, Takashi; Furukawa, Yoshihiro; Kawamura, Fumio; Nakazawa, Hiromoto; Kakegawa, Takeshi
      Astrobiology (2011), 11 (8), 799-813CODEN: ASTRC4; ISSN:1531-1074. (Mary Ann Liebert, Inc.)
      The polymn. of amino acids leading to the formation of peptides and proteins is a significant problem for the origin of life. This problem stems from the instability of amino acids and the difficulty of their oligomerization in aq. environments, such as seafloor hydrothermal systems. We investigated the stability of amino acids and their oligomerization reactions under high-temp. (180-400°C) and high-pressure (1.0-5.5 GPa) conditions, based on the hypothesis that the polymn. of amino acids occurred in marine sediments during diagenesis and metamorphism, at convergent margins on early Earth. Our results show that the amino acids glycine and alanine are stabilized by high pressure. Oligomers up to pentamers were formed, which has never been reported for alanine in the absence of a catalyst. The yields of peptides at a given temp. and reaction time were higher under higher-pressure conditions. Elemental, IR, and isotopic analyses of the reaction products indicated that deamination is a key degrdn. process for amino acids and peptides under high-pressure conditions. A possible NH3-rich environment in marine sediments on early Earth may have further stabilized amino acids and peptides by inhibiting their deamination. Key Words: Origin of life-Peptide formation-Pressure-Deamination. Astrobiol. 11, 799-813.
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    39. 39
      Ohara, S.; Kakegawa, T.; Nakazawa, H. Pressure Effects on the Abiotic Polymerization of Glycine. Origins Life Evol. Biospheres 2007, 37, 215– 223,  DOI: 10.1007/s11084-007-9067-4
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      39
      Pressure Effects on the Abiotic Polymerization of Glycine
      Ohara, Shohei; Kakegawa, Takeshi; Nakazawa, Hiromoto
      Origins of Life and Evolution of Biospheres (2007), 37 (3), 215-223CODEN: OLEBEM; ISSN:0169-6149. (Springer)
      Polymn. expts. were performed using dry glycine under various pressures of 5-100 MPa at 150°C for 1-32 days. The series of expts. was carried out under the assumption that the pore space of deep sediments was adequate for dehydration polymn. of pre-biotic mols. The products show various colors ranging from dark brown to light yellow, depending on the pressure. Visible and IR spectroscopy reveal that the coloring is the result of formation of melanoidins at lower pressures. High-performance liq. chromatog. and mass spectrometry analyses of the products show that: (1) glycine in all the exptl. runs oligomerizes from 2-mer to 10-mer; (2) the yields are dependent on pressure up to 25 MPa and decrease slightly thereafter; and (3) polymn. progressed for the first 8 days, while the amts. of oligomers remained const. for longer-duration runs of up to 32 days. These results suggest that pressure inhibits the decompn. of amino acids and encourages polymn. in the absence of a catalyst. The authors' results further imply that abiotic polymn. could have occurred during diagenesis in deep sediments rather than in oceans.
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      Trifonov, E. N. The Triplet Code from First Principles. J. Biomol. Struct. Dyn. 2004, 22, 1– 11,  DOI: 10.1080/07391102.2004.10506975
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      The triplet code from first principles
      Trifonov, Edward N.
      Journal of Biomolecular Structure & Dynamics (2004), 22 (1), 1-11CODEN: JBSDD6; ISSN:0739-1102. (Adenine Press)
      The temporal order ("chronol.") appearance of amino acids and their resp. codons on evolutionary scene is reconstructed. A consensus chronol. of amino acids was built on the basis of 60 different criteria each offering certain temporal order. After several steps of filtering the chronol. vectors were averaged resulting in the consensus order: Gly, Ala, Asp, Val, Pro, Ser, Glu, (Leu, Thr), Arg, (Ile, Gln, Asn), His, Lys, Cys, Phe, Tyr, Met, Trp. It revealed 2 important features: the amino acids synthesized in imitation expts. of S. Miller (1953, 1987) appeared 1st, whereas the amino acids assocd. with codon capture events came last. The reconstruction of codon chronol. was based on the above consensus temporal order of amino acids, supplemented by the stability and complementarity rules 1st suggested by M. Eigen and P. Schuster (1978), and on the earlier established processivity rule. At no point in the reconstruction was the consensus amino acid chronol. in conflict with these 3 rules. The derived genealogy of all 64 codons suggested several important predictions that were confirmed. The reconstruction of the origin and evolutionary history of the triplet code becomes, thus, a powerful research tool for mol. evolution studies, esp. in its early stages.
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      Longo, L. M.; Blaber, M. Protein design at the interface of the pre-biotic and biotic worlds. Arch. Biochem. Biophys. 2012, 526, 16– 21,  DOI: 10.1016/j.abb.2012.06.009
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      Protein design at the interface of the pre-biotic and biotic worlds
      Longo, Liam M.; Blaber, Michael
      Archives of Biochemistry and Biophysics (2012), 526 (1), 16-21CODEN: ABBIA4; ISSN:0003-9861. (Elsevier B.V.)
      A review. "Proteogenesis" (the origin of proteins) is a likely key event in the unsolved problem of biogenesis (the origin of life). The raw material for the very first proteins comprised the available amino acids produced and accumulated upon the early earth via abiotic chem. and phys. processes. A broad consensus is emerging that this pre-biotic set likely comprised Ala, Asp, Glu, Gly, Ile, Leu, Pro, Ser, Thr, and Val. A key question in proteogenesis is whether such abiotically-produced amino acids comprise a "foldable" set. Current knowledge of protein folding identifies properties of complexity, secondary structure propensity, hydrophobic-hydrophilic patterning, core-packing potential, among others, as necessary elements of foldability. None of these requirements excludes the pre-biotic set of amino acids from being a foldable set. Moreover, nucleophile and metal ion/mineral binding capabilities also appear present in the pre-biotic set. Properties of the pre-biotic set, however, likely restrict foldability to the acidophilic/halophilic environment.
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      Grover, M. A.; He, C. Y.; Hsieh, M.-C.; Yu, S.-S. A Chemical Engineering Perspective on the Origins of Life. Processes 2015, 3, 309– 338,  DOI: 10.3390/pr3020309
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      A chemical engineering perspective on the origins of life
      Grover, Martha A.; He, Christine Y.; Hsieh, Ming-Chien; Yu, Sheng-Sheng
      Processes (2015), 3 (2), 309-338CODEN: PROCCO; ISSN:2227-9717. (MDPI AG)
      Atoms and mols. assemble into materials, with the material structure detg. the properties and ultimate function. Human-made materials and systems have achieved great complexity, such as the integrated circuit and the modern airplane. However, they still do not rival the adaptivity and robustness of biol. systems. Understanding the reaction and assembly of mols. on the early Earth is a scientfic grand challenge, and also can elucidate the design principles underlying biol. materials and systems. This research requires understanding of chem. reactions, thermodn., fluid mechanics, heat and mass transfer, optimization, and control. Thus, the discipline of chem. engineering can play a central role in advancing the field. In this paper, an overview of research in the origins field is given, with particular emphasis on the origin of biopolymers and the role of chem. engineering phenomena. A case study is presented to highlight the importance of the environment and its coupling to the chem.
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      Brack, A.; Ehler, K. W.; Orgel, L. E. N,N′-Carbonyldiimidazole-Induced Diketopiperazine Formation in Aqueous Solution in the Presence of Adenosine-5′-Monophosphate. J. Mol. Evol. 1976, 8, 307– 310,  DOI: 10.1007/bf01739255
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      N,N'-carbonyldiimidazole-induced diketopiperazine formation in aqueous solution in the presence of adenosine-5'-monophosphate
      Brack, A.; Ehler, K. W.; Orgel, L. E.
      Journal of Molecular Evolution (1976), 8 (4), 307-10CODEN: JMEVAU; ISSN:0022-2844.
      3'(2')-O-Glycyladenosine 5'-monophosphate is an intermediate in the conversion of N-[imidazolyl-(1)-carbonyl]glycine to diketopiperazine in the presence of AMP. The significance of these observations to prebiotic chemistry is discussed.
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      Weber, A. L.; Orgel, L. E. The Formation of Peptides from the 2′(3′)-Glycyl Ester of a Nucleotide. J. Mol. Evol. 1978, 11, 189– 198,  DOI: 10.1007/bf01734480
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      The formation of peptides from the 2'(3')-glycyl ester of a nucleotide
      Weber, Arthur L.; Orgel, Leslie E.
      Journal of Molecular Evolution (1978), 11 (3), 189-98CODEN: JMEVAU; ISSN:0022-2844.
      2'(3')-O-(glycyl)-adenosine-5'-(O-methylphosphate), an analog of the 3'-terminus of aminoacylated tRNA, was synthesized. A 3.4M soln. of this compd. maintained at pH 8.2 yielded 5.5% diglycine and 11.5% diketopiperazine, in addn. to the hydrolysis products glycine and adenosine-5'-(O-methylphosphate). Under the same conditions glycine Et ester reacted much more slowly, but ultimately gave similar yields of diglycine and diketopiperazine. The aminolysis of 2'(3')-O-(glycyl)-adenosine-5'-(O-methylphosphate) by free glycine was relatively inefficient, but serine reacted 20 times more rapidly and yielded up to 50% of N-glycylserine. The prebiotic significance of these reactions is discussed.
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      Guo, C.; Holland, G. P. Alanine Adsorption and Thermal Condensation at the Interface of Fumed Silica Nanoparticles: A Solid-State NMR Investigation. J. Phys. Chem. C 2015, 119, 25663– 25672,  DOI: 10.1021/acs.jpcc.5b10236
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      Alanine Adsorption and Thermal Condensation at the Interface of Fumed Silica Nanoparticles: A Solid-State NMR Investigation
      Guo, Chengchen; Holland, Gregory P.
      Journal of Physical Chemistry C (2015), 119 (45), 25663-25672CODEN: JPCCCK; ISSN:1932-7447. (American Chemical Society)
      Studying the interface between biomols. and nanoparticles has attracted considerable attention in recent years since it has great significance in numerous fields including nanotechnol., biomineralization, cancer therapy, and origin of life. The authors present a thorough solid-state NMR study on alanine adsorption and thermal condensation on fumed silica nanoparticles. The structure and dynamics at the interface between alanine and fumed silica nanoparticles were probed with a combination of 1H, 13C, and 15N 1- and two-dimensional (2D) magic angle spinning (MAS) solid-state NMR methods at different alanine surface coverage and hydration levels. It is illustrated at high surface coverage both cryst. and adsorbed states of alanine exist in the samples while only adsorbed alanine is obsd. at low surface coverage (approx. a monolayer). At high hydration levels, the adsorbed alanine exhibits enhanced mobility, and both the carboxyl and amine group interact with mobile water mols. on the silica nanoparticle surface. At low hydration levels, the adsorbed alanine interacts with surface silanols via the protonated amine group and the carboxylate group. The thermal condensation of alanine on fumed silica nanoparticles was also studied, and alanine can undergo thermal condensation at ∼170° at the interface of fumed silica nanoparticles as confirmed by a battery of 13C and 15N 2-dimensional MAS solid-state NMR expts. By combining the adsorption and thermal condensation results, a possible mechanism for the silica surface-catalyzed thermal condensation reaction of alanine is proposed.
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      Campbell, T. D.; Hart, C. A.; Febrian, R.; Cheneler, M. L.; Bracher, P. J. The opposite effect of K+ and Na+ on the hydrolysis of linear and cyclic dipeptides. Tetrahedron Lett. 2018, 59, 2264– 2267,  DOI: 10.1016/j.tetlet.2018.04.073
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      The opposite effect of K+ and Na+ on the hydrolysis of linear and cyclic dipeptides
      Campbell, Thomas D.; Hart, Clara A.; Febrian, Rio; Cheneler, Mark L.; Bracher, Paul J.
      Tetrahedron Letters (2018), 59 (23), 2264-2267CODEN: TELEAY; ISSN:0040-4039. (Elsevier Ltd.)
      Potassium and sodium are generally considered inert 'spectator' ions for org. reactions. Here, we report rate consts. for the acid-promoted hydrolysis of the seven dipeptides of glycine (G) and alanine (A) and an unexpected pattern in how these rates differ in the presence of K+ and Na+. The linear dipeptides hydrolyze 12-18% percent slower in the presence of KCl vs. an equal concn. of NaCl, while the cyclic dipeptides hydrolyze 5-13% faster in the presence of KCl (all P-values < 0.025). We believe this is the first report of a general org. reaction-here, amide hydrolysis-for which some substrates react faster in the presence of K+ and others in Na+. The results offer a potential reason for life's mysterious universal selection of intracellular potassium over sodium.
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      Parker, E. T.; Zhou, M.; Burton, A. S.; Glavin, D. P.; Dworkin, J. P.; Krishnamurthy, R.; Fernández, F. M.; Bada, J. L. A Plausible Simultaneous Synthesis of Amino Acids and Simple Peptides on the Primordial Earth. Angew. Chem., Int. Ed. 2014, 53, 8132– 8136,  DOI: 10.1002/anie.201403683
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      A Plausible Simultaneous Synthesis of Amino Acids and Simple Peptides on the Primordial Earth
      Parker, Eric T.; Zhou, Manshui; Burton, Aaron S.; Glavin, Daniel P.; Dworkin, Jason P.; Krishnamurthy, Ramanarayanan; Fernandez, Facundo M.; Bada, Jeffrey L.
      Angewandte Chemie, International Edition (2014), 53 (31), 8132-8136CODEN: ACIEF5; ISSN:1433-7851. (Wiley-VCH Verlag GmbH & Co. KGaA)
      Following his seminal work in 1953, Stanley Miller conducted an expt. in 1958 to study the polymn. of amino acids under simulated early Earth conditions. In the expt., Miller sparked a gas mixt. of CH4, NH3, and H2O, while intermittently adding the plausible prebiotic condensing reagent cyanamide. For unknown reasons, an anal. of the samples was not reported. We analyzed the archived samples for amino acids, dipeptides, and diketopiperazines by liq. chromatog., ion mobility spectrometry, and mass spectrometry. A dozen amino acids, 10 glycine-contg. dipeptides, and 3 glycine-contg. diketopiperazines were detected. Miller's expt. was repeated and similar polymn. products were obsd. Aq. heating expts. indicate that Strecker synthesis intermediates play a key role in facilitating polymn. These results highlight the potential importance of condensing reagents in generating diversity within the prebiotic chem. inventory.
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      Forsythe, J. G.; Petrov, A. S.; Millar, W. C.; Yu, S.-S.; Krishnamurthy, R.; Grover, M. A.; Hud, N. V.; Fernández, F. M. Surveying the sequence diversity of model prebiotic peptides by mass spectrometry. Proc. Natl. Acad. Sci. U.S.A. 2017, 114, E7652– E7659,  DOI: 10.1073/pnas.1711631114
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      Surveying the sequence diversity of model prebiotic peptides by mass spectrometry
      Forsythe, Jay G.; Petrov, Anton S.; Millar, W. Calvin; Yu, Sheng-Sheng; Krishnamurthy, Ramanarayanan; Grover, Martha A.; Hud, Nicholas V.; Fernandez, Facundo M.
      Proceedings of the National Academy of Sciences of the United States of America (2017), 114 (37), E7652-E7659CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      The rise of peptides with secondary structures and functions would have been a key step in the chem. evolution which led to life. As with modern biol., amino acid sequence would have been a primary determinant of peptide structure and activity in an origins-of-life scenario. It is a commonly held hypothesis that unique functional sequences would have emerged from a diverse soup of proto-peptides, yet there is a lack of exptl. data in support of this. Whereas the majority of studies in the field focus on peptides contg. only one or two types of amino acids, here we used modern mass spectrometry (MS)-based techniques to sep. and sequence de novo proto-peptides contg. broader combinations of prebiotically plausible monomers. Using a dry-wet environmental cycling protocol, hundreds of proto-peptide sequences were formed over a mere 4 d of reaction. Sequence homol. diagrams were constructed to compare exptl. and theor. sequence spaces of tetrameric proto-peptides. MS-based analyses such as this will be increasingly necessary as origins-of-life researchers move toward systems-level investigations of prebiotic chem.
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      Urban, P. L. Quantitative mass spectrometry: an overview. Philos. Trans. R. Soc., A 2016, 374, 20150382,  DOI: 10.1098/rsta.2015.0382
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      Longo, L. M.; Blaber, M. Prebiotic protein design supports a halophile origin of foldable proteins. Front. Microbiol. 2014, 4, 418,  DOI: 10.3389/fmicb.2013.00418
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      Prebiotic protein design supports a halophile origin of foldable proteins
      Longo Liam M; Blaber Michael
      Frontiers in microbiology (2014), 4 (), 418 ISSN:1664-302X.
      There is no expanded citation for this reference.
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      Nelson, K. E.; Robertson, M. P.; Levy, M.; Miller, S. L. Concentration by evaporation and the prebiotic synthesis of cytosine. Origins Life Evol. Biospheres 2001, 31, 221– 229,  DOI: 10.1023/a:1010652418557
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      Concentration by evaporation and the prebiotic synthesis of cytosine
      Nelson, Kevin E.; Robertson, Michael P.; Levy, Matthew; Miller, Stanley L.
      Origins of Life and Evolution of the Biosphere (2001), 31 (3), 221-229CODEN: OLEBEM; ISSN:0169-6149. (Kluwer Academic Publishers)
      The efficient prebiotic synthesis of cytosine from urea and cyanoacetaldehyde (CA) has recently been claimed to be invalid on the basis of possible side reactions of the starting materials and the inapplicability of prebiotic syntheses using drying beach conditions. We therefore have investigated the synthesis of cytosine and uracil from urea and cyanoacetaldehyde at 100° under dry-down conditions, and in soln. at 4° and -20°. We find that cytosine is produced from the low temp. expts. more efficiently than calcd. from the Arrhenius extrapolation from higher temps., i.e., 60-120°. In addn., we find that CA dimer is as efficient as the monomer in cytosine synthesis. We also studied whether evapg. very dil. solns. of nonvolatile org. compds. will conc. according to theory. Solns. as dil. as 10-4 M conc. from pure water approx. according to theory. Similar solns. in 0.5 M NaCl have less than theor. concns. due to absorption, but concns. near dryness were very high.
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      Cech, N. B.; Enke, C. G. Practical implications of some recent studies in electrospray ionization fundamentals. Mass Spectrom. Rev. 2001, 20, 362– 387,  DOI: 10.1002/mas.10008
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      Cech N B; Enke C G
      Mass spectrometry reviews (2001), 20 (6), 362-87 ISSN:0277-7037.
      In accomplishing successful electrospray ionization analyses, it is imperative to have an understanding of the effects of variables such as analyte structure, instrumental parameters, and solution composition. Here, we review some fundamental studies of the ESI process that are relevant to these issues. We discuss how analyte chargeability and surface activity are related to ESI response, and how accessible parameters such as nonpolar surface area and reversed phase HPLC retention time can be used to predict relative ESI response. Also presented is a description of how derivitizing agents can be used to maximize or enable ESI response by improving the chargeability or hydrophobicity of ESI analytes. Limiting factors in the ESI calibration curve are discussed. At high concentrations, these factors include droplet surface area and excess charge concentration, whereas at low concentrations ion transmission becomes an issue, and chemical interference can also be limiting. Stable and reproducible non-pneumatic ESI operation depends on the ability to balance a number of parameters, including applied voltage and solution surface tension, flow rate, and conductivity. We discuss how changing these parameters can shift the mode of ESI operation from stable to unstable, and how current-voltage curves can be used to characterize the mode of ESI operation. Finally, the characteristics of the ideal ESI solvent, including surface tension and conductivity requirements, are discussed. Analysis in the positive ion mode can be accomplished with acidified methanol/water solutions, but negative ion mode analysis necessitates special constituents that suppress corona discharge and facilitate the production of stable negative ions.
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      Torres, A. R.; Alvarez, V. L.; Sandberg, L. B. The Use of o-Phthaldialdehyde in the Detection of Proteins and Peptides. Biochim. Biophys. Acta 1976, 434, 209– 214,  DOI: 10.1016/0005-2795(76)90052-0
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      The use of o-phthaldialdehyde in the detection of proteins and peptides
      Torres, A. R.; Alvarez, V. L.; Sandberg, L. B.
      Biochimica et Biophysica Acta, Protein Structure (1976), 434 (1), 209-14CODEN: BBPTBH; ISSN:0005-2795.
      A highly sensitive (200 ng bovine serum albumin was detectable), automated, fluorometric method that uses o-phthaldialdehyde (I) is described for the detection of peptides and proteins. As an example, the sepn. of bovine serum albumin monomer from oligomers by recycling chromatog. is discussed. A 50-μl sample of serum albumin, eluted from a reverse-flow Sephadex G 100 column, was reacted with a mixt. contg. I and 2-mercaptoethanol in Li borate, (pH 9.2). The fluorescent mixt. then passed through a 4-min delay coil into a flow cell of a fluorometer and then to waste. The excitation and emission wavelengths of the I-fluorescent compds. were 340 and 450 nm, resp. In the case of serum albumin, the response was linearly related to protein concns. of 0.2-120 μg. The effects of various solvents on I fluorescence are covered.
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      Bujdák, J.; Rode, B. M. Silica, alumina and clay catalyzed peptide bond formation: Enhanced efficiency of alumina catalyst. Origins Life Evol. Biospheres 1999, 29, 451– 461,  DOI: 10.1023/a:1006524703513
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      Silica, alumina and clay catalyzed peptide bond formation: enhanced efficiency of alumina catalyst
      Bujdak, Juraj; Rode, Bernd M.
      Origins of Life and Evolution of the Biosphere (1999), 29 (5), 451-461CODEN: OLEBEM; ISSN:0169-6149. (Kluwer Academic Publishers)
      Catalytic efficiencies of clay (hectorite), silica and alumina were tested in peptide bond formation reactions of Gly, Ala, Pro, Val and Leu. The reactions were performed as drying/wetting (hectorite) and temp. fluctuation (silica and alumina) expts. at 85°. The reactivity of amino acids decreased in order Gly > Ala > Pro ≈ Val ≈ Leu. The highest catalytic efficiency was obsd. for alumina, the only catalyst producing oligopeptides in all investigated reaction systems. The peptide bond formation on alumina is probably catalyzed by the same sites and via similar reaction mechanisms as some alumina-catalyzed dehydration reactions used in industrial chem. For these expts., mostly L-amino acids were used, and racemization was not obsd. during peptide bond formations.
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      Yu, S.-S.; Solano, M. D.; Blanchard, M. K.; Soper-Hopper, M. T.; Krishnamurthy, R.; Fernández, F. M.; Hud, N. V.; Schork, F. J.; Grover, M. A. Elongation of Model Prebiotic Proto-Peptides by Continuous Monomer Feeding. Macromolecules 2017, 50, 9286– 9294,  DOI: 10.1021/acs.macromol.7b01569
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      Elongation of model prebiotic proto-peptides by continuous monomer feeding
      Yu, Sheng-Sheng; Solano, Martin D.; Blanchard, Matthew K.; Soper-Hopper, Molly T.; Krishnamurthy, Ramanarayanan; Fernandez, Facundo M.; Hud, Nicholas V.; Schork, F. Joseph; Grover, Martha A.
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      Mixts. of amino acids with hydroxy acids allow for the formation of peptide bonds in a plausible prebiotic scenario via ester bond formation followed by ester-amide exchange. Here, we investigate the ability of the ester-mediated reaction pathway to form even longer polymers with peptide backbones based on the specific details of the reaction protocol. Fresh monomers were fed to the polymer/monomer mixt. periodically by an automated "day-night machine" that was designed to simulate wet-dry cycles that would have been common on the prebiotic Earth. Quant. anal. of peptide bond formation in the complex oligomer mixt. was enabled by a simple hydrolysis treatment. In the ester-mediated peptide elongation process, new monomers add to one end of the chain step-by-step without termination. The feed compn. (hydroxy acids and/or amino acids) was found to det. the final oligomer distribution. Prodn. of longer oligomers enriched in peptide bonds was more efficient when only amino acids were fed because of a smaller no. of active oligomer chains. These results reveal a process for synthesizing longer depsipeptides and/or peptides that could form secondary structures, and possibly functional polymers.
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      BMC Biophysics (2018), 11 (), 2/1-2/15CODEN: BBMIG8; ISSN:2046-1682. (BioMed Central Ltd.)
      The pathways of thermal instability of amino acids have been unknown. New mass spectrometric data allow unequivocal quant. identification of the decompn. products. Calorimetry, thermogravimetry and mass spectrometry were used to follow the thermal decompn. of the eight amino acids G, C, D, N, E, Q, R and H between 185 °C and 280 °C. Endothermic heats of decompn. between 72 and 151 kJ/mol are needed to form 12 to 70% volatile products. This process is neither melting nor sublimation. With exception of cysteine they emit mainly H2O, some NH3 and no CO2. Cysteine produces CO2 and little else. The reactions are described by polynomials, AA → a NH3 + b H2O + c CO2 + d H2S + e residue, with integer or half integer coeffs. The solid monomol. residues are rich in peptide bonds. Eight of the 20 std. amino acids decomp. at well-defined, characteristic temps., in contrast to commonly accepted knowledge. Products of decompn. are simple. The novel quant. results emphasize the impact of water and cyclic condensates with peptide bonds and put constraints on hypotheses of the origin, state and stability of amino acids in the range between 200 °C and 300 °C.
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      The molar absorption coeff., ε, of a protein is usually based on concns. measured by dry wt., nitrogen, or amino acid anal. The studies reported here suggest that the Edelhoch method is the best method for measuring ε for a protein. (This method is described by Gill and von Hippel [1989, Anal Biochem 182:319-326] and is based on data from Edelhoch [1967, Biochem. 6:1948-1954].). The av. ε values for these chromophores in a sample of 18 well-characterized proteins have been estd., and the ε values in water, propanol, 6 M guanidine hydrochloride (GdnHCl), and 8 M urea have been measured. For Trp, the av. ε values for the proteins are intermediate between those measured in 6 M GdnHCl and those measured in propanol. Based on a sample of 116 measured ε values for 80 proteins, the ε at 280 nm of a folded protein in water, ε(280), can best be predicted with this equation L ε(280) (M-1 cm-1) = (#Trp)(5,500) + (#Tyr)(1,490) + (#cystine)(125). These ε(280) values are quite reliable for proteins contg. Trp residues, and less reliable for proteins that do not. However, the Edelhoch method is convenient and accurate, and the best approach is to measure rather than predict ε.
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      Kuipers, Bas J. H.; Gruppen, Harry
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      The molar extinction coeffs. of 20 amino acids and the peptide bond were measured at 214 nm in the presence of acetonitrile and formic acid to enable quant. comparison of peptides eluting from reversed-phase high-performance liq. chromatog., once identified with mass spectrometry (RP-HPLC-MS). The peptide bond has a molar extinction coeff. of 923 M-1 cm-1. Tryptophan has a molar extinction coeff. that is ∼30 times higher than that of the peptide bond, whereas the molar extinction coeffs. of phenylalanine, tyrosine, and histidine are ∼six times higher than that of the peptide bond. Proline, as an individual amino acid, has a negligible molar extinction coeff. However, when present in the peptide chain (except at the N terminus), it absorbs ∼three times more than a peptide bond. Methionine has a similar molar extinction coeff. as the peptide bond, while all other amino acids have much lower molar extinction coeffs. The predictability of the molar extinction coeffs. of proteins and peptides, calcd. by the amino acid compn. and the no. of peptide bonds present, was validated using several proteins and peptides. Most of the measured and calcd. molar extinction coeffs. were in good agreement, which shows that it is possible to compare peptides analyzed by RP-HPLC-MS in a quant. way. This method enables a quant. anal. of all peptides present in hydrolyzates once identified with RP-HPLC-MS.
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      Characterization of Low-Molecular-Weight PLA using HPLC
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      HPLC is applied and assessed as an effective tool to investigate both the prodn. of PLA by polycondensation and its corresponding degrdn. A new HPLC calibration procedure, through which it is possible to fully characterize LMW PLA samples by detg. the concn. of each individual oligomer, is developed. A comparison between HPLC, 1H NMR spectroscopy and non-aq. soln. titrn. is also reported in order to confirm the reliability of the proposed method. Finally, the proposed anal. technique is applied to monitor the development of a polycondensation reaction performed at 150 °C and 133.3 mbar for 12 h.
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    • Material available: additional experimental details of the IP-HPLC method and practical notes for its application, NMR spectra of standards, calibration curves for each Glyn standard, additional IP-HPLC chromatograms, determination of limits of quantitation, and additional references (PDF)


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