MOLECULAR-DYNAMICS SIMULATION OF ANESTHETIC-PHOSPHOLIPID BILAYER INTERACTIONS

To probe the hypothesis of a lipid-mediated mechanism of general anest hetic action on a molecular level, and to help elucidate the nature of the interactions of bioactive compounds with membranes, the effects o f trichloroethylene (TCE), an inhalational general anesthetic, on a di oleoylphosphatidylcholine (DOPC) lipid bilayer have been investigated by molecular dynamics (MD) simulations at 37 degrees C and 1 atm and t he results compared with P-31 and H-2 NMR experimental studies (Ref 1) . The model used included a single TCE molecule embedded in a lipid bi layer consisting of 24 DOPC molecules and an 8 Angstrom layer of expli cit water of solvation in each polar head group region of the bilayer, together with constant-pressure periodic boundary conditions in three dimensions. A comparison of the bilayer properties calculated in the presence and absence of the anesthetic led to the detection of three m ajor perturbations of the bilayer caused by the anesthetic at 1 atm: i ) an increase in the ratio of the effective areas of hydrocarbon tails and the head group per lipid, predicting the tendency of lipids near the anesthetic site of action to form a hexagonal phase (HII); ii) a s light increase in the frequency of chain dihedral angles found in the gauche conformation; and iii) a significant Increase in the lateral me an-square displacement of lipid molecules, an indication of increased lipid lateral diffusion and membrane fluidity. The pressure antagonism of these effects was also studied by MD simulations at pressures of 2 00 and 400 atm. The study of the pressure reversibility of these effec ts at 200 and 400 atm indicated that they were partially prevented at 200 atm and essentially blocked at 400 atm, suggesting their probable relevance to the pressure reversal effect seen with general anesthesia . These results may thus provide insights into the interaction between general anesthetics and similar small organic molecules with membrane s.