Distribution of halothane in a dipalmitoyl phosphatidylcholine bilayer from molecular dynamics calculations

We report a 2-ns constant pressure molecular dynamics simulation of halotha ne, at a mol fraction of 50%, in the hydrated liquid crystal bilayer phase of dipalmitoylphosphatidylcholine. Halothane molecules are found to prefere ntially segregate to the upper part of the lipid acyl chains, with a maximu m probability near the C-5 methylene groups. However, a finite probability is also observed along the tail region and across the methyl trough. Over 9 5% of the halothane molecules are located below the lipid carbonyl carbons, in agreement with photolabeling experiments. Halothane induces lateral exp ansion and a concomitant contraction in the bilayer thickness. A decrease i n the acyl chain segment order parameters, S-CD, for the tail portion, and a slight increase for the upper portion compared to neat bilayers, are in a greement with several NMR studies on related systems. The decrease in S-CD is attributed to a larger accessible volume per lipid in the tail region. S ignificant changes in the electric properties of the lipid bilayer result f rom the structural changes, which include a shift and broadening of the cho line headgroup dipole (P-N) orientation distribution. Our findings reconcil e apparent controversial conclusions from experiments on diverse lipid syst ems.