Conformation of Antamanide

Abstract

The conformation of the cyclic decapeptide antamanide (1) in CDCl3 solution was determined by means of NMR‐spectroscopic methods. Distances obtained from 40 negative NOE values at 500 MHz at low temperature were used as constraints in calculations with the GROMOS molecular dynamics program package to elucidate the most stable backbone conformation in solution. It turned out that there is a fast conformational equilibrium between up to four conformations which differ in a flip about φ and ψ around the two amide bonds Ala4–Phe5 and Phe9–Phe10. Side chain conformations were determined using homo‐ and heteronuclear coupling constants. Carbon relaxation times provide information about the internal flexibility of 1. Three new antamanide derivatives in which Pro3, Pro7, or Pro8 have been substituted by γ‐thiaproline (Thz) were synthesized and crystallized from acetone/water. The X‐ray analyses of these Thz derivatives demonstrate that in the presence of water antamanide adopts a preferred structure which includes four water molecules for building up a compact hydrogen‐bonded structure, which differs from the conformation in chloroform sulution.

Multi-conformational peptide dynamics derived from NMR data: A new search algorithm and its application to antamanide

“…A more recent NMR study of antamanide, combined with restrained MD simulations (Kessler et al, 1988(Kessler et al, , 1989, suggested the presence of two or four different structures in chloroform, one being essentially identical to the X-ray structure (Karle et al, 1979). The rate of this process has however not been determined.…”

The structure of cyclolinopeptide A in chloroform refined by RDC measurements

“…The packing of the Phe side chain over Pro residue was observed, e.g. for antamanide [46], and the mechanism of aromatic-proline CH/π interactions was studied recently [47].…”

On using oscillating time-dependent restraints in MD simulation

“…Antamanide is a cyclic decapeptide for which experimentally measured 3 J HNÀH a -values are available (Kessler et al, 1989). Previous studies using instantaneous restraining have found no single conformation which could explain the 3 J-values measured (Kessler et al, 1988(Kessler et al, , 1989Bru¨schweiler et al, 1991).…”

“…Previous studies using instantaneous restraining have found no single conformation which could explain the 3 J-values measured (Kessler et al, 1988(Kessler et al, , 1989Bru¨schweiler et al, 1991). It was previously used to test J-value restraining methodology (Torda et al, 1993;Scott et al, 1998).…”

“…9 with upper bound as well as lower bound restraining) was applied to enforce 3 J-coupling constants towards the values measured for the peptide antamanide (Kessler et al, 1989), but the results were not very satisfactory (Scott et al, 1998). Therefore, we decided to investigate the particular difficulties of using 3 J-value restraints in structure refinement.…”