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Biophysical Journal 85:3475-3484 (2003)
© 2003 The Biophysical Society

Permeation Across Hydrated DPPC Lipid Bilayers: Simulation of the Titrable Amphiphilic Drug Valproic Acid

Johan Ulander and A. D. J. Haymet

Department of Biochemistry and Chemistry, University of California at San Diego, La Jolla, California; and Commonwealth Scientific and Industrial Research Organization, Marine Research Division, Hobart, Tasmania, Australia

Correspondence: Address reprint requests to J. Ulander, AstraZeneca R&D Mölndal, DMPK & Bioanalytical Chemistry, SE-431 83 Mölndal, Sweden. E-mail: johan.ulander{at}astrazeneca.com.

Valproic acid is a short branched fatty acid used as an anticonvulsant drug whose therapeutic action has been proposed to arise from membrane-disordering properties. Static and kinetic properties of valproic acid interacting with fully hydrated dipalmitoyl phosphatidylcholine lipid bilayers are studied using molecular-dynamics simulations. We calculate spatially resolved free energy profiles and local diffusion coefficients using the distance between the bilayer and valproic acid respective centers-of-mass along the bilayer normal as reaction coordinate. To investigate the pH dependence, we calculate profiles for the neutral valproic acid as well as its water-soluble anionic conjugate base valproate. The local diffusion constants for valproate/valproic acid along the bilayer normal are found to be ~10-6 to 10-5 cm2 s-1. Assuming protonation of valproic acid upon association with—or insertion into—the lipid bilayer, we calculate the permeation coefficient to be ~2.0 10-3 cm s-1, consistent with recent experimental estimates of fast fatty acid transport. The ability of the lipid bilayer to sustain local defects such as water intrusions stresses the importance of going beyond mean field and taking into account correlation effects in theoretical descriptions of bilayer translocation processes.




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