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Binding of Different Cyclosporin Variants to Micelles Evidenced by NMR and MD Simulations.

ABSTRACT: Peptides play a critical role in the life of organisms, performing completely different functions. The biological activity of some peptides, such as cyclosporins, can be determined by the degree of membrane permeability. Thus, it becomes important to study how the molecule interacts with lipid bilayers. Cyclosporins C, E, H and L were characterised molecular dynamics simulation; NMR spectroscopy studies were also carried out for cyclosporins C and E. The comparison of one- and two-dimensional spectra revealed certain similarities between spatial structures of the studied cyclosporin variants. Upon dissolving in water containing DPC micelles, which serve as model membranes, subtle changes in the NMR spectra appear, but in a different way for different cyclosporins. In order to understand whether observed changes are related to any structural modifications, simulation of the interaction of the peptide with the phospholipid micelle was performed. The onset of the interaction was observed, when the peptide is trapped to the surface of the micelle. Simulations of this kind are also of interest in the light of the well-known membrane permeability of cyclosporin, which is important for its biological action.

SUBMITTER: Kobchikova PP

PROVIDER: S-EPMC9965255 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Binding of Different Cyclosporin Variants to Micelles Evidenced by NMR and MD Simulations.

Kobchikova Polina P PP Efimov Sergey V SV Klochkov Vladimir V VV

Membranes 20230205 2

Peptides play a critical role in the life of organisms, performing completely different functions. The biological activity of some peptides, such as cyclosporins, can be determined by the degree of membrane permeability. Thus, it becomes important to study how the molecule interacts with lipid bilayers. Cyclosporins C, E, H and L were characterised molecular dynamics simulation; NMR spectroscopy studies were also carried out for cyclosporins C and E. The comparison of one- and two-dimensional sp ...[more]

PMID: 36837699

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Project description:The 16 EphA and EphB receptors represent the largest family of receptor tyrosine kinases, and their interactions with 9 ephrin-A and ephrin-B ligands initiate bidirectional signals controlling many physiological and pathological processes. Most interactions occur between receptor and ephrins of the same class, and only EphA4 can bind all A and B ephrins. To understand the structural and dynamic principles that enable Eph receptors to utilize the same jellyroll ?-sandwich fold to bind ephrins, the VAPB-MSP domain, peptides and small molecules, we have used crystallography, NMR and molecular dynamics (MD) simulations to determine the first structure and dynamics of the EphA5 ligand-binding domain (LBD), which only binds ephrin-A ligands. Unexpectedly, despite being unbound, the high affinity ephrin-binding pocket of EphA5 resembles that of other Eph receptors bound to ephrins, with a helical conformation over the J-K loop and an open pocket. The openness of the pocket is further supported by NMR hydrogen/deuterium exchange data and MD simulations. Additionally, the EphA5 LBD undergoes significant picosecond-nanosecond conformational exchanges over the loops, as revealed by NMR and MD simulations, but lacks global conformational exchanges on the microsecond-millisecond time scale. This is markedly different from the EphA4 LBD, which shares 74% sequence identity and 87% homology. Consequently, the unbound EphA5 LBD appears to comprise an ensemble of open conformations that have only small variations over the loops and appear ready to bind ephrin-A ligands. These findings show how two proteins with high sequence homology and structural similarity are still able to achieve distinctive binding specificities through different dynamics, which may represent a general mechanism whereby the same protein fold can serve for different functions. Our findings also suggest that a promising strategy to design agonists/antagonists with high affinity and selectivity might be to target specific dynamic states of the Eph receptor LBDs.

Dataset Information

Binding of Different Cyclosporin Variants to Micelles Evidenced by NMR and MD Simulations.

Publications

Binding of Different Cyclosporin Variants to Micelles Evidenced by NMR and MD Simulations.

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