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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| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
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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| Summary: | 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. |
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| ISSN: | 2399-3669 |