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Conformational equilibria of renin inhibitory peptides in solution

Anderson, Graeme James; (1990) Conformational equilibria of renin inhibitory peptides in solution. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Linear peptides exhibit a wide range of conformations in solution at room temperature, all or none of which ray be important in receptor recognition. Resolving these conformations may be a first step towards understanding which conformation(s) is important for binding to receptors, and can lead to the synthesis of more potent conformationally constrained analogues. Spectroscopic methods were used to investigate the conformations adopted by Renin Inhibitory Peptide (RIP), a linear inhibitor of the enzyme renin; renin is an important factor in the regulation of blood pressure, and an attractive target for antihypertensive therapy. Circular dichroism spectra were recorded as a function of solvent polarity, pH, salt concentration and temperature. The low temperature spectra in particular, were useful in resolving the conformational equilibrium - at the lowest temperatures recorded cis amide Pro bonds were 'frozen out'. The room temperature CD spectrum was found, by solvent titrations, to exist as a mixture of two predominant conformations, with cis and trans Pro bonds, the percentage of each conformational component varying as a function of solvent polarity. H HMR studies were used to further define the conformational components of RIP in solution. Assignments were made in the same solvents in which CD spectra were recorded, and structural and 2-D HMR chemical exchange information interpreted in the light of CD results. Low temperature spectra were recorded to attempt to 'freeze out' cis peptide bonds. Energy minimisation and molecular dynamics routines were used to further refine the structures adopted by RIP, based on NMR distance constraints. Overall, the results were consistent with RIP existing as two predominant conformations in equilibruim with one another. This equilibrium was slow relative to the NMR timescale which allowed both conformations to be resolved and the structures of each determined. The low temperature CD studies were crucial for interpretation of the data and can be used quite generally for resolving the conformational components of small flexible peptides.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Conformational equilibria of renin inhibitory peptides in solution
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest
Keywords: Pure sciences
URI: https://discovery.ucl.ac.uk/id/eprint/10111957
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