Effects of Salt on the Structure and Dynamics of the Bis(penicillamine) Enkephalin Zwitterion: A Simulation Study

Molecular dynamics simulations of a zwitterionic bis(penicillamine) enkephalin derivative in 1.0 M saline solution have been performed. Two simulations produced essentially the same average results although they differed in the initial random placement of the salt ions. The dynamical and structural properties from the simulations were compared with those from a previous simulation of the peptide in pure water. The properties of the sodium and chloride ions were compared with those from a simulation of bulk salt solution. An inner-sphere complex between the peptide and the chloride ions was observed in which two to three chloride ions were associated with the NH₃⁺ terminal hydrogen atoms. Several chlorides associated with more than one amide hydrogen simultaneously, and the resulting close chloride-chloride ion contacts were additionally stabilized by bridging water molecules. The sodium ions did not associate directly with the peptide but formed an outer-sphere complex surrounding the peptide-chloride ion complex. The effect of chloride ion association on the structure and dynamics of the peptide was investigated in detail. The spatial correlations between salt ions and the enkephalin derivative are discussed in relation to δ-opioid receptor binding. The implications that the observed ion effects have on our understanding of the Hofmeister series are also considered.