Professor Facundo M. Fernández

Facundo M. Fernández
Regents’ Professor and Vasser-Woolley Chair in Bioanalytical Chemistry, School of Chemistry and Biochemistry, Georgia Institute of Technology
Abstract

Mass Spectrometry and the Origins of Life 

Jay G. Forsythe ¹, Anton S. Petrov ¹, Sheng-Sheng Yu ², Ramanarayanan Krishnamurthy ³, Martha A. Grover ², Nicholas V. Hud ^1,4, Facundo M. Fernandez ^1,4,*

¹ School of Chemistry and Biochemistry, Georgia Institute of Technology.
² School of Chemical & Biomolecular Engineering, Georgia Institute of Technology.
³ Department of Chemistry, The Scripps Research Institute.
⁴ Petit Institute of Bioengineering and Bioscience, Georgia Institute of Technology.
* [email protected]

A pressing question in origins-of-life research is how polypeptides arose from amino acids before the ribosome. In 1953, Miller demonstrated the abiotic synthesis of amino acids in the now-famous spark-discharge experiment¹. Soon after, Fox and Harada began to explore the formation of peptides from amino acids via condensation at high temperatures². These reactions were facilitated by proportionally higher concentrations of amino acids with acidic side chains (e.g., aspartic acid, D) and resulted in the production of “proteinoids,” condensation products containing covalent cross-links not found in coded proteins. In their 1960 manuscript, Fox and Harada speculated about the diversity of proteinoid sequences, yet conceded that “a complete answer to the question of whether the amino acid residues are distributed in a random or other arrangement may require a complete assignment of residues in one molecular species,” a task beyond the analytical capabilities of the time³. 

In subsequent years, the proteinoid concept was displaced by the hypothesis that either RNA or proto-RNA gave rise to life⁴. Nevertheless, to this day, condensation reactions of amino acids are thought to have played a key role in a potentially symbiotic proto-nucleic acid and proto-peptide world⁵. Peptide condensation studies at temperatures lower than those of Fox and Harada, or with the aid of chemical agents, confirmed that abiotic production of peptides was indeed possible, but chain lengths were generally limited to dimers and trimers with low yields⁶. In recent studies, this length barrier has been surpassed, and certain proto-peptides have been shown to form aggregate structures⁷. 

Together with collaborators from the NSF/NASA Center for Chemical Evolution, we introduced a model prebiotic pathway for peptide formation based on ester–amide exchange reactions between α-amino acids and α-hydroxy acids⁸, amino acid structural analogs found in meteorites and model prebiotic reactions⁹. Subjecting these mixtures to sequential hot-dry/cool-wet water evaporation and rehydration cycles led to depsipeptides—peptide-like oligomers containing both amide and ester backbone linkages that were detected by high resolution mass spectrometry. Ester linkages are kinetically and thermodynamically favored but susceptible to hydrolysis, whereas amide linkages are more stable; therefore, depsipeptide sequences became progressively enriched with amide bonds over the course of various dry–wet cycling programs. In the absence of hydroxy acids, peptide bond formation did not spontaneously occur, confirming the plausible role of hydroxy acids as cobuilding blocks of proto-peptides. Successful depsipeptide formation with various amino acid and hydroxy acid monomers and their mixtures was achieved¹⁰, including glycine, glycolic acid, L-alanine, D-alanine, L-lactic acid, L-leucine, and L-serine. These mixtures were investigated using new mass spectrometry approaches inspired by modern proteomic techniques. Additional experients showed that these condensation reactions can be carried out in charged electrosprayed droplets with even higher yields than in batch mode, opening the possibility for proto-peptide formation at a number of prebiotically-relevant interfaces.

References

1. Miller, S. L., A production of amino acids under possible primitive earth conditions. Science 1953, 117 (3046), 528-9.
2. Fox, S. W.; Harada, K., Thermal copolymerization of amino acids to a product resembling protein. Science 1958, 128 (3333), 1214.
3. Fox, S. W.; Harada, K., The Thermal Copolymerization of Amino Acids Common to Protein. J Am Chem Soc 1960, 82 (14), 3745-3751.
4. Hud, N. V.; Cafferty, B. J.; Krishnamurthy, R.; Williams, L. D., The Origin of RNA and "My Grandfather's Axe";. Chem. Biol. 2013, 20 (4), 466-474.
5. Bowman, J.; Hud, N.; Williams, L., The Ribosome Challenge to the RNA World. Journal of Molecular Evolution 2015, 80 (3-4), 143-161.
6. Rode, B. M., Peptide and the origin of life. Peptides 1999, 20 (6), 773-786.
7. Greenwald, J.; Friedmann, M. P.; Riek, R., Amyloid Aggregates Arise from Amino Acid Condensations under Prebiotic Conditions. Angew Chem Int Edit 2016, 55 (38), 11609-11613.
8. Forsythe, J. G.; Yu, S. S.; Mamajanov, I.; Grover, M. A.; Krishnamurthy, R.; Fernandez, 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 Edit 2015, 54 (34), 9871-9875.
9. Peltzer, E. T.; Bada, J. L., Alpha-Hydroxycarboxylic Acids in Murchison Meteorite. Nature 1978, 272 (5652), 443-444.
10. Forsythe, J. G.; Petrov, A. S.; Millar, W. C.; Yu, S. S.; Krishnamurthy, R.; Grover, M. A.; Hud, N. V.; Fernandez, F. M., Surveying the sequence diversity of model prebiotic peptides by mass spectrometry. Proc. Natl. Acad. Sci. U. S. A. 2017, 114 (37), E7652-E7659.

Facundo M. Fernández

Prof. Facundo M. Fernández is the Regents’ Professor and Vasser-Woolley Chair in Bioanalytical Chemistry in the School of Chemistry and Biochemistry at the Georgia Institute of Technology. He received his BSc and MSc in Chemistry from the Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires in 1995, and his PhD in Analytical Chemistry from the same University, in 1999. Between 2000 and 2001, he was a postdoc in the research group of Richard N. Zare in the Department of Chemistry at Stanford University. Between 2002- 2003, he joined the group of Vicki Wysocki in the Department of Chemistry at the University of Arizona as a senior postdoc and then research scientist. Prof. Fernandez is internationally renowned for his work in bioanalytical chemistry, with his research focusing on the development of new tools for assaying small volume samples, tissues, and single cells, and applying such methods to better understanding diseases such as cancer, CF and IBD. He is the author of 220+ peer- reviewed publications, has presented 225+ invited lectures, and graduated 31 Ph.D. and M.Sc. students. He is also the academic director for the Systems Mass Spectrometry Core (SyMS-C) at the Parker H. Petit Institute for Bioengineering and Bioscience at Georgia Tech, where he oversees a portfolio numerous mass spectrometers from most major vendors. He has received several awards, including the NSF CAREER award, the CETL/BP Teaching award, the Ron A. Hites best paper award from the American Society for Mass Spectrometry, and the Beynon award from Rapid Communications in Mass Spectrometry, among others. He serves on the editorial board of The Analyst and as an Associate editor for the Journal of the American Society for Mass Spectrometry and Frontiers in Chemistry. His current research team of 15-20 people is interested in metabolomics, development of new ionization sources, MS imaging, machine learning and ion mobility spectrometry. The research is supported by agencies such as NIH, NSF, NASA, IARPA and DoD. In his free time, he enjoys camping and off-roading with his family, kayaking, and climbing summits to connect with other nerdy people using a tiny ham radio.

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