Solution conformations of cyclosporins and magnesium‐cyclosporin complexes determined by vibrational circular dichroism

Abstract

Vibrational circular dichroism (VCD) spectroscopy was used to investigate the solution conformations of cyclosporins A, C, D, G, and H in CDCl(3), in the amide I and NH/OH-stretching regions, and their corresponding magnesium complexes in CD(3)CN, in the amide I region. VCD spectra are sensitive to the chiral arrangement of Cdbond;O and NH bonds in this cyclic undecapeptide. Calculations of molecular geometries, as well as IR and VCD intensities of model cyclosporin fragments that include the intramolecular hydrogen bonds of the crystal conformations of cyclosporins A and H (CsA and CsH), were carried out at the density functional theory (DFT; BPW91 functional/6-31G* basis set) level. The good agreement between IR and VCD spectra from experiment and DFT calculations provides evidence that the crystal conformation of CsA is dominant in CDCl(3) solution; CsH, however, assumes both an intramolecularly hydrogen-bonded crystal conformation and more open forms in solution. Comparisons of the experimental and calculated VCD spectra in the NH/OH-stretching region of the noncomplexed cyclosporins indicate that conformers with both free and hydrogen-bonded NH and OH groups are present in solution. Differences between the IR and VCD spectra for the metal-free and magnesium-complexed cyclosporins are indicative of strong interactions between cyclosporins and magnesium ions.

Vibrational spectral signatures of peptide secondary structures: N‐methylation and side chain hydrogen bond in cyclosporin A

“…In the present study, the intrinsic spectral signatures of secondary structures somewhat protected by bulky nonpolar alkyl groups should be determined mainly by strong intramolecular H-bonds rather than weak solute-solvent interactions in nonpolar media like chloroform and CCl 4 . As confirmed by recent studies, 10,18 gas-phase DFT calculations are quite good approximate to study the IR and VCD spectra of solute in such cases. For better comparison with the experimental IR and VCD spectra 8,10 in chloroform, the predicted vibrational frequencies are scaled with a common factor of 0.955 while the computed IR and VCD intensities are convoluted with a Gaussian line-shape of 15 cm 21 fwhm.…”

“…6,7 In more polar solvents such as acetonitrile and DMSO, several conformations with more disturbed backbone secondary structures are suggested to exist in equilibrium. [8][9][10] Other conformations in solution have also been suggested, for example, with partial cis-trans isomerization of peptide bonds when interacting with metal ions such as Li 1 , Ca 21 , and Mg 21 , [11][12][13][14] with an intramolecular 1OH. .…”

Optical spectroscopic elucidation of β‐turns in disulfide bridged cyclic tetrapeptides

“…38 Also, like infrared absorption (IR) spectra, VCD spectra of molecules in a particular conformational state can be modeled theoretically using quantum chemical methods. [47][48][49][50][51] VCD spectral characteristics of -turns in linear [52][53][54] and disulfide-cyclized 53 tetrapeptides and longer natural [55][56][57] and model 54,58 sequences have been studied. The VCD spectrum of a disulfide-cyclized type II -turn has been proposed previously by Wyssbrod and Diem.…”

Avian pancreatic polypeptide fragments refold to native aPP conformation when combined in solution: A CD and VCD study

“…[9][10][11][12][13] The chiral sensitivity of VCD is also more effective in demon-strating protein structural changes than is IR spectroscopy. 14,15 EXPERIMENTAL Synthesis, Purification, and Characterization of aPP and Its Fragments aPP, aPP(1-11)-NH 2 , and aPP(12-36) were synthesized on an 432A Peptide Synthesizer (Applied Biosystems, Foster City, CA, USA) in 0.025 mmol scale using Rink AM amide resins. A 3 molar excess of N--Fmoc-protected amino acids was used in each case.…”