Working Paper Article Version 2 This version is not peer-reviewed

D-Amino Acid Substituted Peptides as Potential Alternatives of Homochiral L-Configurations

Version 1 : Received: 28 February 2020 / Approved: 1 March 2020 / Online: 1 March 2020 (03:10:24 CET)
Version 2 : Received: 20 January 2021 / Approved: 21 January 2021 / Online: 21 January 2021 (12:44:27 CET)

How to cite: Shen, J. D-Amino Acid Substituted Peptides as Potential Alternatives of Homochiral L-Configurations. Preprints 2020, 2020030005 Shen, J. D-Amino Acid Substituted Peptides as Potential Alternatives of Homochiral L-Configurations. Preprints 2020, 2020030005


On the primitive Earth, both L- and D-amino acids would have been present. However, only L-amino acids are essential blocks to construct proteins in modern life. To study the relative stability of D-amino acid substituted peptides, a variety of computational methods were applied. Ten prebiotic amino acids (Gly, Ala, Asp, Glu, Ile, Leu, Pro, Ser, Thr, and Val) were previously determined by multiple meteorite, spark discharge, and hydrothermal vent studies. Some previously reported early Earth polypeptide analogs were focused on in this study. Tripeptides composed of only Asp, Ser, and Val exemplified that different positions (i.e., N-terminus, C-terminus, and middle) made a difference in the minimal folding energy of peptides, while the chemical classification of amino acid (hydrophobic, acidic, or hydroxylic) did not show a significant difference. Hierarchical cluster analysis for dipeptides with all possible combinations of the proposed ten prebiotic amino acids and their D-amino acid substituted derivatives generated five clusters. Primordial simple polypeptides were modeled to test the significance of molecular fluctuations, secondary structure occupancies, and folding energy differences based on these clusters. We found peptides with α-helices, long β-sheets, and long loops are usually less sensitive to D-amino acid replacements in comparison to short β-sheets. Intriguingly, amongst 129 D-amino acid residues, mutation sensitivity profiles presented that the ratio of more to less stable residues was about 1. In conclusion, some combinations of a mixture of L- and D-amino acids can potentially act as essential building blocks of life.


D-amino acids; homochirality; molecular modeling; secondary structure occupancy; stability


Biology and Life Sciences, Biochemistry and Molecular Biology

Comments (1)

Comment 1
Received: 21 January 2021
Commenter: Jianxun Shen
Commenter's Conflict of Interests: Author
Comment: This version updated details in methods and discussion to make this article more readable.
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