Simulation of the Structure and Dynamics of the Bis(penicillamine) Enkephalin Zwitterion

We have performed a molecular dynamics simulation of the enkephalin derivative Tyr-(D)Pen-Gly-Phe-(D)Pen (DPDPE) in aqueous solvent. Electrostatic interactions were calculated with the Ewald method so as to accurately model the large interactions between the DPDPE zwitterion and the solvent and to avoid the use of electrostatic cutoff's or neutral chemical blocking groups. DPDPE is found to be extremely constrained with very little variation in the main-chain dihedral angles. Flexibility found in the region of the central glycine is greatly restricted compared with glycines in straight-chain peptides. Several conformational transitions are observed for the two aromatic side chains, indicating a high degree of flexibility in the side chains and that DPDPE does not have a single conformation in solution. This suggests that the arrangement of the tyrosine and phenylalanine aromatic residues in the bound conformation may be selected by the receptor environment. The main-chain conformation of DPDPE in solution has a parallel arrangement of peptide groups. This electrostatically unfavorable structure is stabilized by interactions of the carbonyls with the solvent. Solvent structure around the Ν terminus is found to be considerably localized, involving short ammonium cation to water contacts with lifetimes of the order of 50 ps or more. In comparison, water structure around the C terminus is much more mobile with lifetimes of the order of 20 ps or less.