Solution conformation of a cyclic pentapeptide endothelin antagonist Comparison of structures obtained from constrained dynamics and conformational search

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Abstract
The structure of a cyclic pentapeptide, cyclo-(d-Trp-d-Asp-l-Pro-d-Val-l-Leu), that has high selectivity for the endothelin ETAA receptor has been determined by NMR spectroscopy using constrained molecular dynamics and conformational search procedures. Structures obtained using two methods of refinement, namely (i) constrained molecular dynamics; and (ii) systematic searches of conformational space for optimal satisfaction of distance constraints, were compared to those obtained from systematic searches of conformational space without NMR data. The two different procedures of refinement produce similar conformations that are consistent with the NMR distance constraints. Conformational searches for optimal energy without any NMR distance constraints produced several low-energy structures, two of which have essentially the same backbone as those structures derived from distance-constrained procedures and one of these even reproduces several side-chain positions well. The pentapeptide backbone consists of a linked γ and β-turn conformation, with the leucine and tryptophan as corner residues of the type II β-turn. The side chains are highly ordered both in aqueous solvent and in dimethyl sulfoxide. In aqueous media the leucine side chain is directed towards the indole ring, presumably to reduce the non-polar surface exposure, producing unusual upfield shifts for the methyls (and particularly Hγ). This structural feature was reproduced in one of the structures obtained from conformational searches performed without NMR data. Exhaustive conformational searches appear to provide an alternative method for structure generation for cyclic peptides