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Construction of Cyclic Cell-Penetrating Peptides for Enhanced Penetration of Biological Barriers
Published on: September 19, 2022
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Conformation and Permeability: Cyclic Hexapeptide Diastereomers.
Satoshi Ono1, Matthew R Naylor2, Chad E Townsend2
1Modality Laboratories, Innovative Research Division , Mitsubishi Tanabe Pharma Corporation , 1000 Kamoshida-cho, Aoba-ku , Yokohama , Kanagawa 227-0033 , Japan.
Journal of Chemical Information and Modeling
|May 3, 2019
Summary
Cyclic peptide permeability is linked to structural profiles, not just stereoisomers. Solvent-accessible surface area in cyclohexane predicts cell permeability, guiding the design of new permeable cyclic peptides.
Area of Science:
- Computational chemistry
- Molecular dynamics simulations
- Peptide drug design
Background:
- Understanding the relationship between cyclic peptide structure and cell permeability is crucial for drug development.
- Conformational flexibility and solvent interactions significantly influence peptide behavior in different environments.
Purpose of the Study:
- To analyze the conformational ensembles of cyclic hexapeptide diastereomers using molecular dynamics simulations.
- To investigate the correlation between structural properties and cell permeability/solubility in various solvents.
- To propose a strategy for designing permeable cyclic peptides based on simulation data.
Main Methods:
- Multicanonical molecular dynamics (McMD) simulations were performed for eight cyclic hexapeptide diastereomers.
- Free-energy landscapes (FELs) were generated using molecular shapes and principal component analysis at 300 K.
- Average solvent-accessible surface area (SASA) and polar surface area were calculated and correlated with permeability and solubility.
Main Results:
- Permeable cyclic peptides exhibit distinct structural profiles, even with minor stereoisomeric changes.
- Average SASA in cyclohexane strongly correlated with cell permeability.
- Average SASA in water correlated with aqueous solubility, while polar surface area showed no correlation with permeability.
Conclusions:
- Conformational analysis via McMD simulations provides insights into cyclic peptide permeability.
- SASA in non-polar solvents like cyclohexane is a key predictor of cell permeability.
- FELs can guide the rational design of cell-permeable cyclic peptides.
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