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Updated: Oct 16, 2025
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Development of a Backbone Cyclic Peptide Library as Potential Antiparasitic Therapeutics Using Microwave Irradiation
Published on: January 26, 2016
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Cyclosporin A: Conformational Complexity and Chameleonicity.
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
|October 21, 2021
Summary
Cyclosporin A (CsA) exhibits diverse conformations across various solvents, with simulations revealing its full conformational space. Metal ions appear crucial for CsA
Area of Science:
- Computational chemistry
- Molecular dynamics
- Biophysics
Background:
- Cyclosporin A (CsA) is a crucial immunosuppressant drug.
- Understanding CsA's conformational flexibility is key to its function.
- Previous studies have explored CsA conformations but lacked comprehensive solvent and force field analysis.
Purpose of the Study:
- To investigate the chameleonic behavior of Cyclosporin A (CsA) across diverse solvents.
- To elucidate the conformational ensembles and free-energy landscapes (FELs) of CsA.
- To determine the most accurate force field for describing CsA conformations.
Main Methods:
- Multicanonical molecular dynamics simulations in explicit solvents (water, DMSO, acetonitrile, methanol, chloroform, cyclohexane, n-hexane).
- Utilized multiple AMBER force fields (ff03, 10:EHT, 12:EHT, 14:EHT).
- Analyzed conformational details using free-energy landscapes (FELs) at 300 K and compared with ROESY experimental data.
Main Results:
- Experimentally determined CsA structures represent only a fraction of its total conformational space.
- Simulations revealed similar major conformations in apolar solvents (cyclohexane, n-hexane) as in chloroform, with minor sidechain differences.
- AMBER ff03 force field best reproduced experimentally derived conformations.
Conclusions:
- CsA intrinsically adopts membrane-permeable conformations.
- Metal ions may play a critical role in the cis/trans isomerization of N-methylated amino acids in CsA prior to protein binding.
- The AMBER ff03 force field is recommended for future studies on CsA conformation.
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