Title

Solution conformations of tripeptides and cyclosporins using vibrational circular dichroism and computational methods

Date of Award

2001

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

Advisor(s)

Laurie A. Nafie

Keywords

Solution conformations, Tripeptides, Cyclosporins, Vibrational circular dichroism

Subject Categories

Biochemistry | Biochemistry, Biophysics, and Structural Biology | Chemistry | Life Sciences | Pharmacology | Pharmacology, Toxicology and Environmental Health | Physical Sciences and Mathematics

Abstract

Vibrational circular dichroism (VCD) spectroscopy was used to investigate the solution conformations of a series of protected tripeptides, Z-Ala-Phe-Val-OMe and Z-Ala-Leu-Val-OMe, of DLL, LDL, and LLL configurations, in CCl 4 solutions, at temperatures of 25°C, 5°C, and -5°C in the amide I region, and 25°C and -5°C in the NH-stretching region. Additionally, VCD was used to investigate solution conformations of (1) cyclosporins A, C, D, G, and H in CDCl 3 , in the amide I and NH/OH-stretching regions, and (2) their corresponding magnesium complexes in CD 3 CN, in the amide I region. VCD spectra are sensitive to the chiral arrangement of C=O and NH bonds in intramolecularly hydrogen-bonded conformations. Calculations of geometries and IR and VCD intensities of model cyclosporin fragments, as well as model tripeptides, were carried out at the Hartree-Fock (HF, 6-31G* basis set) and density functional theory (DFT, BPW91 functional/6-31G* basis set) levels. Calculations were also carried out on model dipeptides, only at the HF level.

Solution spectra for the tripeptides indicate that there are multiple conformers present in solution. The LDL tripeptides appear to have only one dominant conformer present as evidenced by similarity in IR and VCD spectra at all temperatures studied. Calculations support that there is only one low energy conformer, a trans C 7 -C 7 ring cis ester orientation. Computational studies on the DLL tripeptides are in agreement with observed data that more than one conformer is present. For the DLL tripeptides, two low energy conformers are present in solution, trans C 7 -C 7 ring cis ester and trans C 5 -C 5 ring cis ester. The VCD spectra provide evidence that the LLL tripeptides aggregate in solution. The appearance of an intense negative low frequency VCD feature in the amide I and NH-stretching regions is indicative of a β-sheet structure. Observed data is reproduced in the DFT calculation for dimer and trimer aggregates. The low energy conformer of the LLL tripeptide is the extended structure, trans C 5 -C 5 ring cis ester, which can undergo self-association.

For the cyclosporins, the good agreement between IR and VCD spectra from experiment and DFT calculation provides evidence that the crystal conformation of cyclosporin A is dominant in CDCl3 solution. Spectra from the NH/OH-stretching region of the free cyclosporins indicate that conformers with both free and hydrogen-bonded NH and OH groups are present in solution. The IR and VCD spectra for the magnesium-complexed cyclosporins are indicative of strong interactions between cyclosporin and magnesium cation.

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