TCB Publications - Abstract
Jeffrey Comer, Klaus Schulten, and Christophe Chipot. Permeability of a fluid lipid bilayer to short-chain alcohols from first principles. Journal of Chemical Theory and Computation, 13:2523-2532, 2017.
s-long free-energy calculations are combined with a recently developed
subdiffusive kinetics framework to describe the membrane permeation of a
homologous series of short-tail alcohols, from methanol to 1-butanol, with
unprecedented fidelity to the underlying molecular models. While the free-
energy profiles exhibit barriers for passage through the center of the bilayer in
all cases, the height of these barriers decreases with the length of the aliphatic
chain of the alcohol, in quantitative agreement with experimentally determined
differential solvation free energies in water and oil. A unique aspect of the
subdiffusive model employed herein, which was developed in a previous article,
is the determination of a position-dependent fractional order, which quantifies
the degree to which the motion of the alcohol deviates from classical diffusion
along the thickness of the membrane. In the aqueous medium far from the
bilayer, this quantity approaches 1.0, the asymptotic limit for purely classical
diffusion, whereas, it dips below 0.75 near the center of the membrane
irrespective of the permeant. Remarkably, the fractional diffusivity near the
center of membrane, where its influence on the permeability is the greatest, is
similar among the four permeants, despite the large difference in molecular
weight and lipophilicity between methanol and 1-butanol. The relative
permeabilities, which are estimated from the free-energy and fractional
diffusivity profiles, are , therefore, determined predominantly by differences in
the former rather than the latter. The predicted relative permeabilities are highly
correlated with existing experimental results , albeit do not agree quantitatively
with them. On the other hand, quite unexpectedly, the experimental
measurements for the homologous series of short-tail alcohols are nearly three
orders of magnitude lower than that for water. Plausible explanations for this
apparent disagreement between theory and experiment are considered in detail.
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