Structural Model of a Cyclic Dynorphin A Analog Bound to Dodecylphosphocholine Micelles by NMR and Restrained Molecular Dynamics

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Abstract
The compound c[Cys5,11]dynorphin A-(1−11)-NH2, 1, is a cyclic dynorphin A analog that shows similar selectivity and potency at the κ-opioid receptor when compared to the native form of the peptide in central nervous system assays. Previous molecular mechanics calculations have shown that the ring portion of the isoform that is trans about the Arg9−Pro10 ω bond contains either a β-turn from residues Arg6 to Arg9 or an α-helical conformation. Our results from solution state NMR indicate that the compound exhibits cis−trans isomerism about the Arg9−Pro10 ω bond in both aqueous solution and when bound to dodecylphosphocholine micelles. Restrained molecular dynamics calculations show that the cis isoform of the peptide contains a type III β-turn from residues Arg7 to Pro10. Similar calculations on the trans isoform show it to contain a β-turn from residues Cys5 and Arg8. In this report we describe the generation of three-dimensional models from NMR data for the ring portions of both the cis and trans isoforms of 1 bound to dodecylphosphocholine micelles. Comparison with other dynorphin A structural information indicates that both the cis and trans isoforms of the peptide may be active as κ-opioid agonists.

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