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Characterization of the bioactive form and molecular determinants of recognition of cyclic enkephalin peptides at the δ‐opioid receptor
Author(s) -
Chew Clifford,
Villar Hugo O.,
Loew Gilda H.
Publication year - 1993
Publication title -
biopolymers
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.556
H-Index - 125
eISSN - 1097-0282
pISSN - 0006-3525
DOI - 10.1002/bip.360330414
Subject(s) - chemistry , conformational isomerism , enkephalin , stereochemistry , molecular recognition , folding (dsp implementation) , structural similarity , opioid receptor , molecular mechanics , molecule , molecular dynamics , crystallography , receptor , computational chemistry , opioid , biochemistry , organic chemistry , electrical engineering , engineering
An extensive and systematic search strategy to determine the conformational profile of 12 cyclic disulfide‐bridged opioid peptides with varying affinities at the δ receptor has been carried out to identify the structure that is recognized by the δ receptor for each analogue. The methods and procedures used here for the conformational search have already been validated for [ D ‐Pen2, D ‐Pen5] enkephalin (DPDPE), one member of this family. Use of these methods led to a low‐energy solution conformation of DPDPE in excellent agreement with all the geometric properties deduced from its solution nmr spectra. Each of the analogue was subjected to the same procedure, involving a combination of molecular dynamics simulations at high and low temperature. The study was repeated in two environmental conditions, an apolar environment, simulated by using a distance‐dependent dielectric constant, and a polar environment by embedding the peptides in a high constant dielectric ( ε = 80). An automated comparison of the different conformers based on their backbone rms and average distance between the key aromatic moieties was followed by graphic analysis using maximum structural overlap. The cross‐comparison of the conformations for each analogue revealed a unique conformer that may be recognized by the δ receptor for each high‐affinity analogue that permitted maintaining the critical elements required for recognition in a simple spatial orientation, while maximizing similarity in other regions. © 1993 John Wiley & Sons, Inc.