Conformational relevant NMR parameters such as NOE values and coupling constants depend in a nonlinear way on distances and dihedral angles. This may be misleading in the determination of molecular conformations when a conformational equilibrium exists with rates that are fast on the NMR time scale: short nuclear distances are overemphasized when distances obtained by NOEs are used as a tool for modelling the conformation in solution. Antamanide, a cyclic decapeptide, is shown to be such a case. However, molecular dynamics calculations with NOE constraints can be used to identify crucial NOE values and prove the evidence of a conformational equilibrium. In addition, homonuclear and heteronuclear coupling constants provide additional support for the existence of "the" conformation or the conformational equilibrium, respectively.
The conformation of the cyclic decapeptide antamanide (1) in CDCl3 solution was determined by means of NMR‐spectroscopic methods. Distances obtained from 40 negative NOE values at 500 MHz at low temperature were used as constraints in calculations with the GROMOS molecular dynamics program package to elucidate the most stable backbone conformation in solution. It turned out that there is a fast conformational equilibrium between up to four conformations which differ in a flip about φ and ψ around the two amide bonds Ala4–Phe5 and Phe9–Phe10. Side chain conformations were determined using homo‐ and heteronuclear coupling constants. Carbon relaxation times provide information about the internal flexibility of 1. Three new antamanide derivatives in which Pro3, Pro7, or Pro8 have been substituted by γ‐thiaproline (Thz) were synthesized and crystallized from acetone/water. The X‐ray analyses of these Thz derivatives demonstrate that in the presence of water antamanide adopts a preferred structure which includes four water molecules for building up a compact hydrogen‐bonded structure, which differs from the conformation in chloroform sulution.
The dependence of the conformation of cyclosporin A (CPA), a cyclic undecapeptide with potent immunosuppressive activity, on the type of solvent environment is examined using the computer simulation method of molecular dynamics (MD). Conformational and dynamic properties of CPA in aqueous solution are obtained from MD simulations of a CPA molecule dissolved in a box with water molecules. Corresponding properties of CPA in apolar solution are obtained from MD simulations of CPA in a box with carbontetrachloride. The results of these simulations in H2O and in CCl4 are compared to each other and to those of previous simulations of crystalline CPA and of an isolated CPA molecule. The conformation of the backbone of the cyclic polypeptide is basically independent of the type of solvent. In aqueous solution the beta-pleated sheet is slightly weaker and the gamma-turn is a bit less pronounced than in apolar solution. Side chains may adopt different conformations in different solvents. In apolar solution the hydrophobic side chain of the MeBmt residue is in an extended conformation with its hydroxyl group hydrogen bonded to the backbone carbonyl group. In aqueous solution this hydrophobic side chain folds over the core of the molecule and the mentioned hydrogen bond is broken in favor of hydrogen bonding to water molecules. The conformation obtained from the MD simulation in CCl4 nicely agrees with experimental atom-atom distance data as obtained from nmr experiments in chloroform. In aqueous solution the relaxation of atomic motion tends to be slower than in apolar solution.
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 C alpha 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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