Page 5 of 13
Journal of the American Chemical Society
Figure 3. Selective accumulation of prebiotic phospholipids via energy-dissipative cycling. a) Scheme of the acylation-hydrolysis cycles. b)
Stability of 10a-d towards hydrolysis. c) Membranes made of mixed acylglycerol-2-phosphates were observed from the second acylation-
hydrolysis round.
1
2
3
4
5
In accordance with the cycling model proposed herein
(Figure 3a), when 7 was subjected to multiple rounds of
acylation with 8a-d and hydrolysis, the mixture became
Notes
The authors declare no competing financial interest.
6
7
8
progressively enriched in the longer-chain amphiphiles (9d and
10d), at the expense of the shorter-chain species (9a-c and 10a-
c), with concomitant formation of vesicles.
ACKNOWLEDGMENT
This work was supported by the Medical Research Council (Grant
No. MC_UP_A024_1009) and a grant from the Simons Foundation
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
CONCLUSIONS
The non-enzymatic energy-dissipative conversion of non-
assembling species into membrane self-assembling
amphiphiles could represent a plausible pathway to drive the
(Grant No. 290362 to J.D.S.). We thank A. N. Albertsen, D. J.
Ritson, D. A. Russell and other J.D.S. group members for fruitful
discussions.
evolution of phospholipids towards those used by biology35,36
.
REFERENCES
Here we have presented an effective pathway for the selection
of self-assembling amphiphiles from a library of diverse chain-
length acylating reactants. Motivated by our observation of the
prebiotic formation of glycerol phosphates, we investigated the
acylation chemistry of these phospholipid precursors. We
showed that C8-C10 acylglycerol-2-phosphates form stable
membranes, which exhibit enhanced encapsulation efficiency
and stability towards pH and temperature with respect to
membranes made solely of fatty acids of analogous chain
length. Phospholipid selection is achieved through multiple
rounds of acylation and hydrolysis, which allow for membrane
formation as the self-assembling species accumulate.
(1)
Lombard, J.; López-García, P.; Moreira, D. The early evolution
of lipid membranes and the three domains of life. Nat. Rev.
Microbiol. 2012, 10, 507.
(2)
(3)
Blain, J. C.; Szostak, J. W. Progress Toward Synthetic Cells.
Annu. Rev. Biochem. 2014, 83, 615.
Monnard, P. A.; Deamer, D. W. Membrane self-assembly
processes: Steps toward the first cellular life. Anat. Rec. 2002,
268, 196.
(4)
(5)
Chen, I. A.; Walde, P. From self-assembled vesicles to protocells.
Cold Spring Harb. Perspect. Biol. 2010, 2, a002170.
Mansy, S. S.; Szostak, J. W. Reconstructing the emergence of
cellular life through the synthesis of model protocells. Cold
Spring Harb. Symp. Quant. Biol. 2009, 74, 47.
(6)
(7)
(8)
McCollom, T. M.; Ritter, G.; Simoneit, B. R. T. Lipid Synthesis
Under Hydrothermal Conditions by Fischer-Tropsch-Type
Reactions. Orig. Life Evol. Biosph. 1999, 29, 153.
We have previously observed that backbone-heterogeneous
RNA oligomers might have undergone proofreading to
overcome the inherent lack of regiocontrol in the
oligomerization step through energy-dissipative recycling19.
Similarly, iterative rounds of acylation and hydrolysis could be
exploited to directly select for self-assembling phospholipids
from a heterogeneous mixture of amphiphiles. The energetic
cost of this optimization process is met by the hydrolytic
turnover of acylating agents. The ideal scenario to promote
acylation and hydrolysis processes might have emerged from a
set of closely related geochemical settings29 or geophysical
scenarios involving fluctuations in bulk conditions, e.g. pH,
temperature and salt concentrations, such as those described in
Mißbach, H.; Schmidt, B. C.; Duda, J. P.; Lünsdorf, N. K.; Goetz,
W.; Thiel, V. Assessing the diversity of lipids formed via Fischer-
Tropsch-type reactions. Org. Geochem. 2018, 119, 110.
Mansy, S. S.; Schrum, J. P.; Krishnamurthy, M.; Tobé, S.; Treco,
D. A.; Szostak, J. W. Template-directed synthesis of a genetic
polymer in a model protocell. Nature 2008, 454, 122.
Adamala, K.; Szostak, J. W. Nonenzymatic template-directed
RNA synthesis inside model protocells. Science 2013, 342, 1098.
Budin, I.; Debnath, A.; Szostak, J. W. Concentration-driven
growth of model protocell membranes. J. Am. Chem. Soc. 2012,
134, 20812.
(9)
(10)
(11)
(12)
Zhu, T. F.; Szostak, J. W. Coupled growth and division of model
protocell membranes. J. Am. Chem. Soc. 2009, 131, 5705.
Apel, C. L.; Deamer, D. W. The formation of glycerol
open rock pores37,38
.
monodecanoate by
a
dehydration/condensation reaction:
Although the identification of prebiotically plausible
acylating agents for the formation of acylglycerol-phosphates
still represents an open challenge in prebiotic chemistry, our
findings delineate a potential route that could have driven the
transition towards biological phospholipids on the early Earth.
Increasing the chemical complexity of amphiphiles on the early
earth. Orig. Life Evol. Biosph. 2005, 35 (4), 323.
(13)
(14)
(15)
Maurer, S. E.; Nguyen, G. Prebiotic Vesicle Formation and the
Necessity of Salts. Orig. Life Evol. Biosph. 2016, 46 (2–3), 215.
Joyce, G. F.; Szostak, J. W. Protocells and RNA Self-Replication.
Cold Spring Harb. Perspect. Biol. 2018, 10, a034801.
Bonfio, C.; Godino, E.; Corsini, M.; Fabrizi de Biani, F.; Guella,
G.; Mansy, S. S. Prebiotic iron–sulfur peptide catalysts generate
a pH gradient across model membranes of late protocells. Nat.
Catal. 2018, 1, 616.
ASSOCIATED CONTENT
Supporting Information. Materials, methods, compound
characterization, supplementary figures and tables are available
Experimental details, compound characterization,
supplementary figures and tables.
(16)
(17)
(18)
(19)
(20)
Jin, L.; Kamat, N. P.; Jena, S.; Szostak, J. W. Fatty
Acid/Phospholipid Blended Membranes:
A
Potential
Intermediate State in Protocellular Evolution. Small 2018, 14, 1.
Budin, I.; Prwyes, N.; Zhang, N.; Szostak, J. W. Chain-length
heterogeneity allows for the assembly of fatty acid vesicles in
dilute solutions. Biophys. J. 2014, 107, 1582.
Ruiz-Mirazo, K.; Briones, C.; de la Escosura, A. Prebiotic
Systems Chemistry: New Perspectives for the Origins of Life.
Chem. Rev. 2014, 114, 285.
Mariani, A.; Sutherland, J. D. Non-Enzymatic RNA Backbone
Proofreading through Energy-Dissipative Recycling. Angew.
Chem. Int. Ed. 2017, 56, 6563.
AUTHOR INFORMATION
Corresponding Author
* johns@mrc-lmb.cam.ac.uk.
Author Contributions
§ These authors contributed equally.
Harayama, T.; Riezman, H. Understanding the diversity of
ACS Paragon Plus Environment