Prebiotic alternatives to proteins: Structure and function of hyperbranched polyesters
Abstract
Proteins are responsible multiple biological functions, such as ligand binding, catalysis, and ion channeling. This functionality is enabled by proteins' three-dimensional structures that require long polypeptides. Since plausibly prebiotic synthesis of functional polypeptides has proven challenging in the laboratory, we propose that these functions may have been initially performed by alternative macromolecular constructs, namely hyperbranched polymers (HBPs), during early stages of chemical evolution. HBPs can be straightforwardly synthesized in one-pot processes, possess globular structures determined by their architecture as opposed to folding in proteins, and have documented ligand binding and catalytic properties. Our initial study focuses on glycerol-citric acid HBPs synthesized via moderate heating in the dry state. The polymerization products consisted of a mixture of isomeric structures of varying molar mass as evidenced by NMR, mass spectrometry and size-exclusion chromatography. Addition of divalent cations during polymerization resulted in increased incorporation of citric acid into the HBPs and the possible formation of cation-oligomer complexes. The chelating properties of citric acid govern the makeup of the resulting polymer, turning the polymerization system into a rudimentary smart material.
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Branched polymers have been considered as possible precursors to globular proteins and enzymes.
“Such branched polymers have been considered as possible precursors to globular proteins [36] and enzymes [39].”
From Polyesters as a Model System for Building Primitive Biologies from Non-Biological Prebiotic Chemistry (2020) · cites this paper as [36]
Polyesters have a considerably lower energy for bond formation (~0 kcal mol−1) and have been considered as possible ancestral precursors of peptides.
“Alternatively, polyesters, which have a considerably lower energy for bond formation (~0 kcal mol−1 [54]), have been considered as possible ancestral precursors of peptides [36,55].”
From Polyesters as a Model System for Building Primitive Biologies from Non-Biological Prebiotic Chemistry (2020) · cites this paper as [36]
Cites
Hyperbranched polymers: from synthesis to applications
Gao, C., & Yan, D. (2004) · Progress in Polymer Science · doi:10.1016/j.progpolymsci.2003.12.002 · Cited by 2,046 · see citing works
Molecular Size Distribution in Three Dimensional Polymers. I. Gelation 1
Flory, P. J. (1941) · Journal of the American Chemical Society · doi:10.1021/ja01856a061 · Cited by 1,924 · see citing works
Organic Compound Synthesis on the Primitive Earth
Miller, S. L., & Urey, H. C. (1959) · Science · doi:10.1126/science.130.3370.245 · Cited by 1,403 · see citing works
Dendritic Catalysts and Dendrimers in Catalysis
Astruc, D., & Chardac, F. (2001) · Chemical Reviews · doi:10.1021/cr010323t · Cited by 1,062 · see citing works
Synthesis of long prebiotic oligomers on mineral surfaces.
Ferris, J. P., Hill, A. R., Liu, R., & Orgel, L. E. (1996) · Nature · doi:10.1038/381059a0 · Cited by 865 · see citing works
Flory, P. J. (1952) · Journal of the American Chemical Society · doi:10.1021/ja01131a008 · Cited by 801 · see citing works
Review of State of Art of Smart Structures and Integrated Systems
Chopra, I. (2002) · AIAA Journal · doi:10.2514/2.1561 · Cited by 788 · see citing works
Racemic amino acids from the ultraviolet photolysis of interstellar ice analogues
Bernstein, M. P., Dworkin, J. P., Sandford, S. A., Cooper, G. W., & Allamandola, L. J. (2002) · Nature · doi:10.1038/416401a · Cited by 782 · see citing works
Self-citationWater soluble hyperbranched polyphenylene: "a unimolecular micelle?"
Kim, Y. H., & Webster, O. W. (1990) · Journal of the American Chemical Society · doi:10.1021/ja00167a094 · Cited by 707 · see citing works
Molecular Size Distribution in Three Dimensional Polymers. II. Trifunctional Branching Units
Flory, P. J. (1941) · Journal of the American Chemical Society · doi:10.1021/ja01856a062 · Cited by 546 · see citing works
Hyperbranched Aliphatic Polyesters
Malmstroem, E., Johansson, M., & Hult, A. (1995) · Macromolecules · doi:10.1021/ma00109a049 · Cited by 502 · see citing works
Carbonaceous meteorites as a source of sugar-related organic compounds for the early Earth
Cooper, G., Kimmich, N., Belisle, W., Sariñana, J., Brabham, K., & Garrel, L. (2001) · Nature · doi:10.1038/414879a · Cited by 481 · see citing works
On the Mechanism of the Formose Reaction
Breslow, R. (1959) · Tetrahedron Letters · doi:10.1016/s0040-4039(01)99487-0 · Cited by 456 · see citing works
Molecular Size Distribution in Three Dimensional Polymers. III. Tetrafunctional Branching Units
Flory, P. J. (1941) · Journal of the American Chemical Society · doi:10.1021/ja01856a063 · Cited by 450 · see citing works
Drug complexation, in vitro release and cellular entry of dendrimers and hyperbranched polymers
Kolhe, P. (2003) · International Journal of Pharmaceutics · doi:10.1016/s0378-5173(03)00225-4 · Cited by 416 · see citing works
Dendrimer-Metalloporphyrins: Synthesis and Catalysis
Bhyrappa, P., Young, J. K., Moore, J. S., & Suslick, K. S. (1996) · Journal of the American Chemical Society · doi:10.1021/ja953474k · Cited by 393 · see citing works
Lahav, N., White, D., & Chang, S. (1978) · Science · doi:10.1126/science.663639 · Cited by 381 · see citing works
The origin of intermediary metabolism
Morowitz, H. J., Kostelnik, J. D., Yang, J. J., & Cody, G. D. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.110153997 · Cited by 338 · see citing works
Self-citationPrabaharan, M., Grailer, J. J., Pilla, S., Steeber, D. A., & Gong, S. (2009) · Biomaterials · doi:10.1016/j.biomaterials.2009.02.011 · Cited by 317 · see citing works
Thermal Copolymerization of Amino Acids to a Product Resembling Protein
Fox, S. W., & Harada, K. (1958) · Science · doi:10.1126/science.128.3333.1214 · Cited by 292 · see citing works
Functionalized Amphiphilic Hyperbranched Polymers for Targeted Drug Delivery
Chen, S., Zhang, X., Cheng, S., Zhuo, R., & Gu, Z. (2008) · Biomacromolecules · doi:10.1021/bm800371n · Cited by 258 · see citing works
Interstellar Antifreeze: Ethylene Glycol
Hollis, J. M., Lovas, F. J., Jewell, P. R., & Coudert, L. H. (2002) · The Astrophysical Journal · doi:10.1086/341148 · Cited by 217 · see citing works
α-Hydroxycarboxylic acids in the Murchison meteorite
Peltzer, E. T., & Bada, J. L. (1978) · Nature · doi:10.1038/272443a0 · Cited by 171 · see citing works
Template-Directed Synthesis with Adenosine-5′-phosphorimidazolide
Weimann, B. J., Lohrmann, R., Orgel, L. E., Schneider-Bernloehr, H., & Sulston, J. E. (1968) · Science · doi:10.1126/science.161.3839.387 · Cited by 166 · see citing works
Cascade polymers. 35. pH dependence of hydrodynamic radii of acid-terminated dendrimers
Newkome, G. R., Young, J. K., Baker, G. R., Potter, R. L., Audoly, L., Cooper, D., Weis, C. D., Morris, K. F., & Johnson, C. S. (1993) · Macromolecules · doi:10.1021/ma00061a041 · Cited by 157 · see citing works
A biodegradable thermoset polymer made by esterification of citric acid and glycerol
Halpern, J. M., Urbanski, R., Weinstock, A. K., Iwig, D. F., Mathers, R. T., & von Recum, H. A. (2013) · Journal of Biomedical Materials Research Part A · doi:10.1002/jbm.a.34821 · Cited by 155 · see citing works
Ribosome-catalyzed ester formation
Fahnestock, S. R., Neumann, H., Shashoua, V. E., & Rich, A. (1970) · Biochemistry · doi:10.1021/bi00814a013 · Cited by 147 · see citing works
Wooley, K. L., Hawker, C. J., Lee, R., & Fréchet, J. M. J. (1994) · Polymer Journal · doi:10.1295/polymj.26.187 · Cited by 144 · see citing works
Cooper, G., Reed, C., Nguyen, D. T., Carter, M., & Wang, Y. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1105715108 · Cited by 131 · see citing works
Cody, G. D., Boctor, N. Z., Hazen, R. M., Brandes, J. A., Morowitz, H. J., & Yoder, H. S. (2001) · Geochimica et Cosmochimica Acta · doi:10.1016/s0016-7037(01)00674-3 · Cited by 130 · see citing works
Self-citationSome consequences of the RNA world hypothesis
Orgel, L. E. (2003) · Origins of life and evolution of the biosphere · doi:10.1023/a:1024616317965 · Cited by 124 · see citing works
Kinetics of Formation of Hyperbranched Polyesters Based on 2,2-Bis(methylol)propionic Acid
Malmström, E., & Hult, A. (1996) · Macromolecules · doi:10.1021/ma951084c · Cited by 122 · see citing works
Mamajanov, I., MacDonald, P. J., Ying, J., Duncanson, D. M., Dowdy, G. R., Walker, C. A., Engelhart, A. E., Fernández, F. M., Grover, M. A., Hud, N. V., et al. (2014) · Macromolecules · doi:10.1021/ma402256d · Cited by 115 · see citing works
Self-citationRibosome-Catalyzed Polyester Formation
Fahnestock, S. R., & Rich, A. S. (1971) · Science · doi:10.1126/science.173.3994.340 · Cited by 113 · see citing works
Kirkorian, K., Ellis, A., & Twyman, L. J. (2012) · Chemical Society Reviews · doi:10.1039/c2cs35238a · Cited by 105 · see citing works
Dendrimeric Pyridoxamine Enzyme Mimics
Liu, L., & Breslow, R. (2003) · Journal of the American Chemical Society · doi:10.1021/ja0374473 · Cited by 98 · see citing works
Fréchet, J. M. J., & Hawker, C. J. (1995) · Reactive and Functional Polymers · doi:10.1016/1381-5148(95)00010-d · Cited by 86 · see citing works
Biodegradable Hyperbranched Polyglycerol with Ester Linkages for Drug Delivery
Hu, M. L., Chen, M., Li, G., Pang, Y., Wang, D., Wu, J., Qiu, F., Zhu, X., & Sun, J. L. (2012) · Biomacromolecules · doi:10.1021/bm300966d · Cited by 83 · see citing works
Water-Soluble Degradable Hyperbranched Polyesters: Novel Candidates for Drug Delivery?
Gao, C., Xu, Y., Yan, D., & Chen, W. (2003) · Biomacromolecules · doi:10.1021/bm025738i · Cited by 82 · see citing works
Kienle, R. H., van der Meulen, P. A., & Petke, F. E. (1939) · Journal of the American Chemical Society · doi:10.1021/ja01878a001 · Cited by 80 · see citing works
Sagi, V. N., Punna, V., Hu, F., Meher, G., & Krishnamurthy, R. (2012) · Journal of the American Chemical Society · doi:10.1021/ja211383c · Cited by 76 · see citing works
A comparative study of the hydroxy acids from the Murchison, GRA 95229 and LAP 02342 meteorites
Pizzarello, S., Wang, Y., & Chaban, G. M. (2010) · Geochimica et Cosmochimica Acta · doi:10.1016/j.gca.2010.08.013 · Cited by 75 · see citing works
Structural Diversities of Cobalt(II) Coordination Polymers with Citric Acid
Zhou, Z., Deng, Y., & Wan, H. (2005) · Crystal Growth & Design · doi:10.1021/cg0496282 · Cited by 74 · see citing works
Hedwig, G., Liddle, J., & Reeves, R. K. H. (1980) · Australian Journal of Chemistry · doi:10.1071/ch9801685 · Cited by 63 · see citing works
Ricardo, A., Frye, F., Carrigan, M. A., Tipton, J. D., Powell, D. H., & Benner, S. A. (2006) · The Journal of Organic Chemistry · doi:10.1021/jo061770h · Cited by 58 · see citing works
Changa, D. M. (1983) · Journal of the American Oil Chemists Society · doi:10.1007/bf02679800 · Cited by 57 · see citing works
Interaction of the Ni2+ ion with citric acid in an aqueous solution
Zelenin, O. Y. (2007) · Russian Journal of Coordination Chemistry · doi:10.1134/s1070328407050065 · Cited by 54 · see citing works
Schwendinger, M. G., Tattler, R., Saetia, S., Liedl, K. R., Kroemer, R. T., & Rode, B. M. (1995) · Inorganica Chimica Acta · doi:10.1016/0020-1693(94)04186-y · Cited by 52 · see citing works
Butch, C., Cope, E. D., Pollet, P., Gelbaum, L., Krishnamurthy, R., & Liotta, C. L. (2013) · Journal of the American Chemical Society · doi:10.1021/ja405103r · Cited by 46 · see citing works
Stability constant of the calcium-citrate(3-) ion pair complex
Singh, R. P., Yeboah, Y. D., Pambid, E. R., & Debayle, P. (1991) · Journal of Chemical & Engineering Data · doi:10.1021/je00001a015 · Cited by 36 · see citing works
Non-enzymic synthesis of deoxyadenylate oligonucleotides on a polyuridylate template
Schneider-Bernloehr, H., Lohrmann, R., Sulston, J., Weimann, B. J., Orgel, L. E., & Miles, H. T. (1968) · Journal of Molecular Biology · doi:10.1016/0022-2836(68)90079-x · Cited by 33 · see citing works
Amino acid activation with adenosine 5′-phosphorimidazolide
Weber, A. L., & Orgel, L. E. (1978) · Journal of Molecular Evolution · doi:10.1007/bf01768020 · Cited by 31 · see citing works
Efficient Oligomerization of Negatively-Charged β-Amino Acids at −20 °C
Liu, R., & Orgel, L. E. (1997) · Journal of the American Chemical Society · doi:10.1021/ja9702529 · Cited by 27 · see citing works
Thermal synthesis and hydrolysis of polyglyceric acid
Weber, A. (2005) · Origins of life and evolution of the biosphere · doi:10.1007/bf01808284 · Cited by 27 · see citing works
Metal chelates of citric acid as corrosion inhibitors for zinc pigment
Müller, B., Kläger, W., & Kubitzki, G. (1997) · Corrosion Science · doi:10.1016/s0010-938x(97)00061-9 · Cited by 22 · see citing works
Williams, R. J., Gabriel, A., & Andrews, R. C. (1928) · Journal of the American Chemical Society · doi:10.1021/ja01392a005 · Cited by 11 · see citing works
Thermal synthesis of internucleotide phosphodiester linkages
Schwartz, A. W., & Fox, S. W. (1964) · Biochimica et Biophysica Acta (BBA) - Specialized Section on Nucleic Acids and Related Subjects · doi:10.1016/0926-6550(64)90290-7 · Cited by 11 · see citing works
Mechanism of hydration and dehydration reactions in presence of zinc halides
Kuchkarev, A. B., & Shuikin, N. I. (1956) · Russian Chemical Bulletin · doi:10.1007/bf01177533 · Cited by 4 · see citing works
Free energies and equilibria of peptide bond hydrolysis and formation.
Martin, R. B. (1998) · Biopolymers · doi:10.1002/(sici)1097-0282(19980415)45:5
Tasaka (2001) · doi:10.1002/1521-3927(20010701)22:11
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- Authors
- Mamajanov, I., Callahan, M. P., Dworkin, J. P., & Cody, G. D.
- Affiliations
- Carnegie Institution for Science (US)
- Goddard Space Flight Center (US)
- Corresponding author
- Mamajanov, Irena
- Venue
- Origins of Life and Evolution of Biospheres
- Published
- 2015-05-20
- Volume
- 45
- Issue
- 1-2
- Pages
- 123-137
- ISSN
- 0169-6149 (ISSN-L)
- 1573-0875
- OpenAlex
- W316426083
- Cited by
- 17
- References
- 60
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 3 · 2023: 3 · 2022: 1 · 2020: 3 · 2019: 3 · 2017: 2
- FWCI
- 0.43
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Origins of Life and Evolution of Biospheres (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Physical Sciences › Materials Science › Polymers and Plastics › Dendrimers and Hyperbranched Polymers
- Physical Sciences › Physics and Astronomy › Astronomy and Astrophysics › Origins and Evolution of Life
- Physical Sciences › Chemistry › Organic Chemistry › Advanced Polymer Synthesis and Characterization
- Keywords
- hyperbranched polyester, prebiotic chemistry, chemical evolution, divalent cations, ligand binding, catalytic activity, chelation, smart materials
- MeSH terms
- Origin of Life, Cations, Divalent, Glycerol, Polyesters, Temperature, Molecular Structure, Citric Acid, Evolution, Chemical, Polymerization
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