Conformational analysis of cyclolinopeptide A, a cyclic nonapeptide: nuclear overhauser effect and energy minimization studies

Abstract

The conformation of cyclolinopeptide A [cyclo(Pro-Pro-Phe-Phe-Leu-Ile-Ile-Leu-Val)], a naturally occurring cyclic nonapeptide has been investigated in dimethylsulfoxide solution by 270 MHz ¹H-nmr. A complete assignment of all C^αH and NH resonances has been accomplished using two-dimensional correlated spectroscopy and nuclear Overhauser effects (NOEs). Analysis of interresidue NOEs and J_HNCα_H values permit construction of a molecular model for the cyclic peptide backbone. The crude model derived from nmr has been used as a starting point for energy minimization, which yields a refined structure largely compatible with nmr observations. The major features of the conformation of cyclolinopeptide A are a Type VI β-turn centered at Pro(1)-Pro(2), with a cis peptide bond between these residues and a γ-turn (C₇) structure centered at Ile(6). Two intramolecular hydrogen bonds Val(9) CO - Phe(3)NH (4 →1) and Leu(5) CO - Ile(7)NH (3 → 1) are observed in the low-energy conformation. The limited solvent accessibility observed for the Val(9) and Leu(5) NH groups in the nmr studies are rationalized in terms of steric shielding.