Structural Ensemble of the Insulin Monomer.
Journal
Biochemistry
ISSN: 1520-4995
Titre abrégé: Biochemistry
Pays: United States
ID NLM: 0370623
Informations de publication
Date de publication:
26 10 2021
26 10 2021
Historique:
pubmed:
13
10
2021
medline:
30
11
2021
entrez:
12
10
2021
Statut:
ppublish
Résumé
Experimental evidence suggests that monomeric insulin exhibits significant conformational heterogeneity, and modifications of apparently disordered regions affect both biological activity and the longevity of pharmaceutical formulations, presumably through receptor binding and fibrillation/degradation, respectively. However, a microscopic understanding of conformational heterogeneity has been lacking. Here, we integrate all-atom molecular dynamics simulations with an analysis pipeline to investigate the structural ensemble of human insulin monomers. We find that 60% of the structures present at least one of the following elements of disorder: melting of the A-chain N-terminal helix, detachment of the B-chain N-terminus, and detachment of the B-chain C-terminus. We also observe partial melting and extension of the B-chain helix and significant conformational heterogeneity in the region containing the B-chain β-turn. We then estimate hydrogen-exchange protection factors for the sampled ensemble and find them in line with experimental results for KP-insulin, although the simulations underestimate the importance of unfolded states. Our results help explain the ready exchange of specific amide sites that appear to be protected in crystal structures. Finally, we discuss the implications for insulin function and stability.
Identifiants
pubmed: 34637307
doi: 10.1021/acs.biochem.1c00583
pmc: PMC8552439
doi:
Substances chimiques
Insulin
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
3125-3136Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM118774
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM136381
Pays : United States
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