Conformation analysis and molecular modelling of cyclic hexapeptides
Conformation analysis and molecular modelling of cyclic hexapeptides
With the recent discovery that the binding proteins of Cyclosporin A (1) and FK506 (2) exhibit peptidyl proly cis - trans isomerase activity, interest has grown in the synthesis of more potent and selective inhibitors of these enzymes in order to better control the immune response. However relatively little is known about the factors controlling the ratio of cis and trans isomers of the Prom imide bond, and the activation barrier to interconversion between these isomers. In this regard a study of the effect of changing the chirality of the i+ 2 residue when Pro is in the i+ 1 position in a β - turn was made. The synthesis of cyclic hexapeptides cyclo(Pro -DPhe - Gly - Val - Tyr - Gin) (13) and cyclo (Pro - LPhen - Gly- Val - Tyr - Gin) (14) is described. Analysis of the solution conformations of 13 and 14 in DMSO - per by 1 and 2D proton NMR is then made. Two distinct conformations are observed for both peptides, in the ratio of ca. 95:5 for 13 and 65:35 for 14. The major component in each case is due to the trans imide isomer Pro while the minor component incorporates the cis isomer. For 13 the major conformation (28) exhibits a type II β-turn conformation for the LPro - DPHE dipeptide segment, as predicted by the empirical rules of turn formation. Surprisingly the major component of 14 (30) also shows a type II turn conformation about the LPro - LPHE region, in contrast to the type Iβ-turn expected. Measurement of the energy barrier to interconversion between the NMR conformations by saturation transfer, in conjunction with molecular mechanics energy calculations, indicates that the isomer ratio difference between 13 and 14 is due to stabilisation of the trans isomer 28 by ca. 6.8 kJ.mol relative to the trans isomer 30. Systematic searching and restrained molecular dynamics investigations indicate that this energy difference is due to enthalpic ring strain induced by the unfavourable type IIβ-turn conformation about LPro - LPHe in 30. Furthermore these calculations suggest that the exclusive formation of this turn type is due to solvation of the LPro-LPHe amide NH in DMSO. In addition a dynamic model describing amide NH temperature dependence as observed by 1H NMR is presented.
University of Southampton
1990
Collins, Nathanael
(1990)
Conformation analysis and molecular modelling of cyclic hexapeptides.
University of Southampton, Doctoral Thesis.
Record type:
Thesis
(Doctoral)
Abstract
With the recent discovery that the binding proteins of Cyclosporin A (1) and FK506 (2) exhibit peptidyl proly cis - trans isomerase activity, interest has grown in the synthesis of more potent and selective inhibitors of these enzymes in order to better control the immune response. However relatively little is known about the factors controlling the ratio of cis and trans isomers of the Prom imide bond, and the activation barrier to interconversion between these isomers. In this regard a study of the effect of changing the chirality of the i+ 2 residue when Pro is in the i+ 1 position in a β - turn was made. The synthesis of cyclic hexapeptides cyclo(Pro -DPhe - Gly - Val - Tyr - Gin) (13) and cyclo (Pro - LPhen - Gly- Val - Tyr - Gin) (14) is described. Analysis of the solution conformations of 13 and 14 in DMSO - per by 1 and 2D proton NMR is then made. Two distinct conformations are observed for both peptides, in the ratio of ca. 95:5 for 13 and 65:35 for 14. The major component in each case is due to the trans imide isomer Pro while the minor component incorporates the cis isomer. For 13 the major conformation (28) exhibits a type II β-turn conformation for the LPro - DPHE dipeptide segment, as predicted by the empirical rules of turn formation. Surprisingly the major component of 14 (30) also shows a type II turn conformation about the LPro - LPHE region, in contrast to the type Iβ-turn expected. Measurement of the energy barrier to interconversion between the NMR conformations by saturation transfer, in conjunction with molecular mechanics energy calculations, indicates that the isomer ratio difference between 13 and 14 is due to stabilisation of the trans isomer 28 by ca. 6.8 kJ.mol relative to the trans isomer 30. Systematic searching and restrained molecular dynamics investigations indicate that this energy difference is due to enthalpic ring strain induced by the unfavourable type IIβ-turn conformation about LPro - LPHe in 30. Furthermore these calculations suggest that the exclusive formation of this turn type is due to solvation of the LPro-LPHe amide NH in DMSO. In addition a dynamic model describing amide NH temperature dependence as observed by 1H NMR is presented.
This record has no associated files available for download.
More information
Published date: 1990
Identifiers
Local EPrints ID: 461894
URI: http://eprints.soton.ac.uk/id/eprint/461894
PURE UUID: ccd013e8-9e62-4016-8a3f-5a39b78ef200
Catalogue record
Date deposited: 04 Jul 2022 18:58
Last modified: 04 Jul 2022 18:58
Export record
Contributors
Author:
Nathanael Collins
Download statistics
Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.
View more statistics