Selective peptide bond formation via side chain reactivity and self-assembly of abiotic phosphates
Abstract In the realm of biology, peptide bonds are formed via reactive phosphate-containing intermediates, facilitated by compartmentalized environments that ensure precise coupling and folding. Herein, we use aminoacyl phosphate esters, synthetic counterparts of biological aminoacyl adenylates, th...
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| Format: | Article |
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Nature Portfolio
2025-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56432-6 |
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| author | Arti Sharma Kun Dai Mahesh D. Pol Ralf Thomann Yi Thomann Subhra Kanti Roy Charalampos G. Pappas |
| author_facet | Arti Sharma Kun Dai Mahesh D. Pol Ralf Thomann Yi Thomann Subhra Kanti Roy Charalampos G. Pappas |
| author_sort | Arti Sharma |
| collection | DOAJ |
| description | Abstract In the realm of biology, peptide bonds are formed via reactive phosphate-containing intermediates, facilitated by compartmentalized environments that ensure precise coupling and folding. Herein, we use aminoacyl phosphate esters, synthetic counterparts of biological aminoacyl adenylates, that drive selective peptide bond formation through side chain-controlled reactivity and self-assembly. This strategy results in the preferential incorporation of positively charged amino acids from mixtures containing natural and non-natural amino acids during the spontaneous formation of amide bonds in water. Conversely, aminoacyl phosphate esters that lack assembly and exhibit fast reactivity result in random peptide coupling. By introducing structural modifications to the phosphate esters (ethyl vs. phenyl) while retaining aggregation, we are able to tune the selectivity by incorporating aromatic amino acid residues. This approach enables the synthesis of sequences tailored to the specific phosphate esters, overcoming limitations posed by certain amino acid combinations. Furthermore, we demonstrate that a balance between electrostatic and aromatic stacking interactions facilitates covalent self-sorting or co-assembly during oligomerization reactions using unprotected N-terminus aminoacyl phosphate esters. These findings suggest that self-assembly of abiotic aminoacyl phosphate esters can activate a selection mechanism enabling the departure from randomness during the autonomous formation of amide bonds in water. |
| format | Article |
| id | doaj-art-8602e8cd2f7a49d5a24246ea9641e627 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-8602e8cd2f7a49d5a24246ea9641e6272025-02-09T12:45:11ZengNature PortfolioNature Communications2041-17232025-02-0116111010.1038/s41467-025-56432-6Selective peptide bond formation via side chain reactivity and self-assembly of abiotic phosphatesArti Sharma0Kun Dai1Mahesh D. Pol2Ralf Thomann3Yi Thomann4Subhra Kanti Roy5Charalampos G. Pappas6FIT – Freiburg Center for Interactive Materials and Bioinspired Technologies, University of FreiburgDFG Cluster of Excellence livMatS @FIT – Freiburg Center for Interactive Materials and Bioinspired Technologies, University of FreiburgInstitute of Organic Chemistry, University of FreiburgFIT – Freiburg Center for Interactive Materials and Bioinspired Technologies, University of FreiburgFIT – Freiburg Center for Interactive Materials and Bioinspired Technologies, University of FreiburgInstitute of Organic Chemistry, University of FreiburgFIT – Freiburg Center for Interactive Materials and Bioinspired Technologies, University of FreiburgAbstract In the realm of biology, peptide bonds are formed via reactive phosphate-containing intermediates, facilitated by compartmentalized environments that ensure precise coupling and folding. Herein, we use aminoacyl phosphate esters, synthetic counterparts of biological aminoacyl adenylates, that drive selective peptide bond formation through side chain-controlled reactivity and self-assembly. This strategy results in the preferential incorporation of positively charged amino acids from mixtures containing natural and non-natural amino acids during the spontaneous formation of amide bonds in water. Conversely, aminoacyl phosphate esters that lack assembly and exhibit fast reactivity result in random peptide coupling. By introducing structural modifications to the phosphate esters (ethyl vs. phenyl) while retaining aggregation, we are able to tune the selectivity by incorporating aromatic amino acid residues. This approach enables the synthesis of sequences tailored to the specific phosphate esters, overcoming limitations posed by certain amino acid combinations. Furthermore, we demonstrate that a balance between electrostatic and aromatic stacking interactions facilitates covalent self-sorting or co-assembly during oligomerization reactions using unprotected N-terminus aminoacyl phosphate esters. These findings suggest that self-assembly of abiotic aminoacyl phosphate esters can activate a selection mechanism enabling the departure from randomness during the autonomous formation of amide bonds in water.https://doi.org/10.1038/s41467-025-56432-6 |
| spellingShingle | Arti Sharma Kun Dai Mahesh D. Pol Ralf Thomann Yi Thomann Subhra Kanti Roy Charalampos G. Pappas Selective peptide bond formation via side chain reactivity and self-assembly of abiotic phosphates Nature Communications |
| title | Selective peptide bond formation via side chain reactivity and self-assembly of abiotic phosphates |
| title_full | Selective peptide bond formation via side chain reactivity and self-assembly of abiotic phosphates |
| title_fullStr | Selective peptide bond formation via side chain reactivity and self-assembly of abiotic phosphates |
| title_full_unstemmed | Selective peptide bond formation via side chain reactivity and self-assembly of abiotic phosphates |
| title_short | Selective peptide bond formation via side chain reactivity and self-assembly of abiotic phosphates |
| title_sort | selective peptide bond formation via side chain reactivity and self assembly of abiotic phosphates |
| url | https://doi.org/10.1038/s41467-025-56432-6 |
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