title: Study of procaine and tetracaine in the lipid bilayer using molecular dynamics simulation.
abstract: Despite available experimental results, the molecular mechanism of action of local anesthetics upon the nervous system and contribution of the cell membrane to the process are still controversial. In this work, molecular dynamics simulations were performed to investigate the effect of two clinically used local anesthetics, procaine and tetracaine, on the structure and dynamics of a fully hydrated dimyristoylphosphatidylcholine lipid bilayer. We focused on comparing the main effects of uncharged and charged drugs on various properties of the lipid membrane: mass density distribution, diffusion coefficient, order parameter, radial distribution function, hydrogen bonding, electrostatic potential, headgroup angle, and water dipole orientation. To compare the diffusive nature of anesthetic through the lipid membrane quantitatively, we investigated the hexadecane/water partition coefficient using expanded ensemble simulation. We predicted the permeability coefficient of anesthetics in the following order: uncharged tetracaine > uncharged procaine > charged tetracaine > charged procaine. We also shown that the charged forms of drugs are more potent in hydrogen bonding, disturbing the lipid headgroups, changing the orientation of water dipoles, and increasing the headgroup electrostatic potential more than uncharged drugs, while the uncharged drugs make the lipid diffusion faster and increase the tail order parameter. The results of these simulation studies suggest that the different forms of anesthetics induce different structural modifications in the lipid bilayer, which provides new insights into their molecular mechanism.
authors.affiliation: Department of Chemistry, K. N. Toosi University of Technology, Tehran, P.O. Box 15875-4416, Iran. sjalili@kntu.ac.ir.|Computational Physical Sciences Research Laboratory, School of Nano-Science, Institute for Research in Fundamental Sciences (IPM), Tehran, P.O. Box 19395-5531, Iran. sjalili@kntu.ac.ir.|Chemical Physics Theory Group, Department of Chemistry, University of Toronto, 80 Saint George Street, Toronto, Ontario, M5S 3H6, Canada. sjalili@kntu.ac.ir.
authors.forename: Seifollah
authors.initials: S
authors.lastname: Jalili
authors.affiliation: Department of Chemistry, K. N. Toosi University of Technology, Tehran, P.O. Box 15875-4416, Iran.
authors.forename: Marzieh
authors.initials: M
authors.lastname: Saeedi
mesh_terms: D000779:Anesthetics, Local / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D002462:Cell Membrane / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D004058:Diffusion; D004134:Dimyristoylphosphatidylcholine / Q000378:metabolism; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism*; D008968:Molecular Conformation; D056004:Molecular Dynamics Simulation; D011343:Procaine / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D013748:Tetracaine / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D013816:Thermodynamics
chemical_list: D000779:Anesthetics, Local; D008051:Lipid Bilayers; D013748:Tetracaine; D011343:Procaine; D004134:Dimyristoylphosphatidylcholine
keywords: DMPC membrane; Drug-membrane interaction; Expanded ensemble simulation; Local anesthetics; Molecular dynamics simulation; Solvation free energy