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Molecular dynamics simulations of cyclosporin A: The crystal structure and dynamic modelling of a structure in apolar solution based on NMR data

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The conformation of the immunosuppressive drug cyclosporin A (CPA), both in apolar solution and in crystalline state, has been studied by computer simulation techniques. Three molecular dynamics (MD) simulations have been performed: one modelling the crystal structure and two modelling the structure in apolar solution, using a restrained MD approach in which data from nuclear magnetic resonance (NMR) and infrared (IR) spectroscopy are taken into account. The simulation of the crystalline state (MDC) concerns a system of 4 unit cells containing 16 cyclosporin A molecules and 22 water molecules, which is simulated using crystalline periodic boundary conditions. The simulations modelling the apolar solvent conformation (MDS) concern one isolated cyclosporin A molecule. In these simulations an extra term in the interatomic potential function is used, which forces the molecule to satisfy a set of 57 atom-atom distance constraints originating from nuclear Overhauser effects (NOEs) obtained from NMR spectroscopy and one distance constraint deduced from IR spectroscopy.

From a comparison of the results of the crystal simulation to those of the X-ray experiment in terms of structure, atomic fluctuations, hydrogen bond pattern, etc., it is concluded that the force field that is used yields an adequate representation of crystalline cyclosporin A. Secondly, it is shown that the dynamic modelling technique that is used to obtain a structure in a polar solution from NMR distance information works well. Starting from initial conformations which have a root mean square difference of 0.14 nm both distance restrained MD simulations converge to the same final solution structure. A comparison of the crystal structure of cyclosporin A and the one in apolar solution shows that there are significant differences. The overall difference in atomic positions is 0.09 nm for the Cx atoms and 0.17 nm for all atoms. In apolar solution, the molecule is slightly more bent and the side chains of 1 MeBmt and 10 MeLeu adopt a different conformation.

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Molecular dynamics


Energy minimization


Molecular dynamics simulation of the crystal


Restrained molecular dynamics simulation to obtain the structure in solution starting from the crystal structure


Like MDS1, but starting from the SMS structure


Proposed structure in solution, obtained by model building


An X-ray structure


Cyclosporin A


Nuclear magnetic resonance spectroscopy


Nuclear Overhauser enhancement

MDS1 :

Mean simulated structure obtained by averaging over the time period 20–40 ps of the MDS1 simulation


Mean simulated structure obtained by averaging over the time period 10–30 ps of the MDS2 simulation


Mean simulated structure obtained by averaging over the time period 7–15 ps and over the 16 asymmetric units in the computational box of the MDC simulation.


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Correspondence to J. Lautz.

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Lautz, J., Kessler, H., Kaptein, R. et al. Molecular dynamics simulations of cyclosporin A: The crystal structure and dynamic modelling of a structure in apolar solution based on NMR data. J Computer-Aided Mol Des 1, 219–241 (1987). https://doi.org/10.1007/BF01677046

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Key words

  • Cyclosporin A
  • Restrained molecular dynamics simulation
  • NOE