Characterization of the bioactive form and molecular determinants of recognition of cyclic enkephalin peptides at the delta-opioid receptor.
An extensive and systematic search strategy to determine the conformational profile of 12 cyclic disulfide-bridged opioid peptides with varying affinities at the delta receptor has been carried out to identify the structure that is recognized by the delta 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 (epsilon = 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 delta 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.
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Molecular Research Institute, Palo Alto, California 94304.
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D000595:Amino Acid Sequence; D020881:Enkephalin, D-Penicillamine (2,5)-; D004745:Enkephalins / Q000737:chemistry* / Q000378:metabolism; D008969:Molecular Sequence Data; D010456:Peptides, Cyclic / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D017465:Receptors, Opioid, delta / Q000378:metabolism*; D013816:Thermodynamics
D004745:Enkephalins; D010456:Peptides, Cyclic; D017465:Receptors, Opioid, delta; D020881:Enkephalin, D-Penicillamine (2,5)-