Kinetic, thermodynamic, and ab initio insights of AsnGly isomerisation as a ticking time bomb for protein integrity
Abstract Under physiological conditions in peptides or proteins, the -AsnGly- motif autonomously rearranges within hours/days to β-Asp and α-Asp containing sequence, via succinimide intermedier. The formation of the succinimide is the rate-limiting step, with a strong pH and temperature dependence....
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-12-01
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| Series: | Communications Chemistry |
| Online Access: | https://doi.org/10.1038/s42004-024-01374-1 |
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| author | Fruzsina Pilhál Imre Jákli Ernő Keszei András Láng András Perczel |
| author_facet | Fruzsina Pilhál Imre Jákli Ernő Keszei András Láng András Perczel |
| author_sort | Fruzsina Pilhál |
| collection | DOAJ |
| description | Abstract Under physiological conditions in peptides or proteins, the -AsnGly- motif autonomously rearranges within hours/days to β-Asp and α-Asp containing sequence, via succinimide intermedier. The formation of the succinimide is the rate-limiting step, with a strong pH and temperature dependence. We found that Arg(+) at the (n + 2) position (relative to Asn in the nth position) favors isomerisation by forming a transition-state like structure, whereas Glu(-) disfavors isomerisation by adopting a β-turn like conformer. Four to six key intermediate structures (proton transfer, transition-state formation, ring-closure and ammonia-release steps) have been identified along the intrinsic reaction coordinate pathways. We explain how, under the right conditions, the N-atom of a backbone amide, hardly a potent nucleophile, can nevertheless initiate isomerisation. The new data are useful for the design of self-structuring motifs, more resistant protein backbones, antibodies, etc. |
| format | Article |
| id | doaj-art-662c1042012b4c8faf92d73412eea979 |
| institution | OA Journals |
| issn | 2399-3669 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Chemistry |
| spelling | doaj-art-662c1042012b4c8faf92d73412eea9792025-08-20T01:59:44ZengNature PortfolioCommunications Chemistry2399-36692024-12-017111310.1038/s42004-024-01374-1Kinetic, thermodynamic, and ab initio insights of AsnGly isomerisation as a ticking time bomb for protein integrityFruzsina Pilhál0Imre Jákli1Ernő Keszei2András Láng3András Perczel4Laboratory of Structural Chemistry and Biology, Institute of Chemistry, ELTE Eötvös Loránd UniversityLaboratory of Structural Chemistry and Biology, Institute of Chemistry, ELTE Eötvös Loránd UniversityDepartment of Physical Chemistry and Chemical Kinetics Laboratory, Institute of Chemistry, ELTE Eötvös Loránd UniversityLaboratory of Structural Chemistry and Biology, Institute of Chemistry, ELTE Eötvös Loránd UniversityLaboratory of Structural Chemistry and Biology, Institute of Chemistry, ELTE Eötvös Loránd UniversityAbstract Under physiological conditions in peptides or proteins, the -AsnGly- motif autonomously rearranges within hours/days to β-Asp and α-Asp containing sequence, via succinimide intermedier. The formation of the succinimide is the rate-limiting step, with a strong pH and temperature dependence. We found that Arg(+) at the (n + 2) position (relative to Asn in the nth position) favors isomerisation by forming a transition-state like structure, whereas Glu(-) disfavors isomerisation by adopting a β-turn like conformer. Four to six key intermediate structures (proton transfer, transition-state formation, ring-closure and ammonia-release steps) have been identified along the intrinsic reaction coordinate pathways. We explain how, under the right conditions, the N-atom of a backbone amide, hardly a potent nucleophile, can nevertheless initiate isomerisation. The new data are useful for the design of self-structuring motifs, more resistant protein backbones, antibodies, etc.https://doi.org/10.1038/s42004-024-01374-1 |
| spellingShingle | Fruzsina Pilhál Imre Jákli Ernő Keszei András Láng András Perczel Kinetic, thermodynamic, and ab initio insights of AsnGly isomerisation as a ticking time bomb for protein integrity Communications Chemistry |
| title | Kinetic, thermodynamic, and ab initio insights of AsnGly isomerisation as a ticking time bomb for protein integrity |
| title_full | Kinetic, thermodynamic, and ab initio insights of AsnGly isomerisation as a ticking time bomb for protein integrity |
| title_fullStr | Kinetic, thermodynamic, and ab initio insights of AsnGly isomerisation as a ticking time bomb for protein integrity |
| title_full_unstemmed | Kinetic, thermodynamic, and ab initio insights of AsnGly isomerisation as a ticking time bomb for protein integrity |
| title_short | Kinetic, thermodynamic, and ab initio insights of AsnGly isomerisation as a ticking time bomb for protein integrity |
| title_sort | kinetic thermodynamic and ab initio insights of asngly isomerisation as a ticking time bomb for protein integrity |
| url | https://doi.org/10.1038/s42004-024-01374-1 |
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