Molecular Dynamics Investigations of Structure and Dynamics of Lipid Bilayers and Associated Anesthetics

Abstract: Detailed understanding of lipid bilayers are of tremendous importance due to their role in many biological processes. This Thesis focuses on structural and dynamical properties of lipid bilayers and their interactions with locally acting anesthetics, studied by Molecular Dynamics simulations.The effect of dehydration of a lipid bilayer is a biologically important phenomenon which was investigated by detailed examination of a number of structural and dynamical lipid parameters at different levels of hydration. The result shows that whereas the structural properties of the bilayer only moderately depend on the degree of hydration, the dynamics of the system is affected very strongly.Related to changes in the bilayer caused by hydration are structural and dynamical changes caused by the presence of anesthetics. Lidocaine is a common, locally acting anesthetic that interacts with lipid bilayers. The difference in position, orientation and diffusional behavior for charged and uncharged lidocaine was examined. The overall results indicate a rather restricted motion, determined by the lipids for the charged lidocaine, whereas the uncharged molecules are more free to diffuse in the lateral direction, as well as able to cross the bilayer.For membrane associated anesthetics, the effect on the bilayer electrostatic potential when introducing anesthetic compounds could contribute to the anesthetic effect. When the change in electrostatic potential and headgroup orientation was examined, both properties were found to be changed by charged as well as uncharged lidocaine. Surprisingly, the potentials in the middle part of the bilayer were almost the same for the charged and uncharged form of lidocaine. The suggested explanation for this is that the uncharged lidocaine gives a significant contribution to the electrostatic potential due to its orientation.Knowledge about the three dimensional structure and structural changes of the lipids in a bilayer is an important biological question. The validity of a method based on the additive potential and maximum entropy model applied to a lipid bilayer was investigated by comparing distributions for two torsion angles extracted from simulations with their corresponding distributions received from the combined model. The results indicates that this new method could be used as a tool for interpretation of experimental data in bilayer systems.For better correspondence with experiment, a calibration of the CHARMM force field was conducted by changing interactions in the lipid tails and charges in the lipid head group. With these new parameters, the simulations gave a fraction of gauche conformations in the lipid tails close to the experimentally determined value, and a very good experimental agreement for the area per lipid, electron density, X-ray structure factor, and NMR order parameters.