Jeffrey Comer, Klaus Schulten, and Christophe Chipot.
Diffusive models of membrane permeation with explicit orientational
freedom.
Journal of Chemical Theory and Computation, 10:2710-2718,
2014.
COME2014A
Accurate calculation of permeabilities from first-principles has been a long-standing
challenge for computer simulations, notably in the context of drug discovery, as a route to
predict the propensity of small, organic molecules to spontaneously translocate
biological membranes. Of equal importance is the understanding of the permeation
process and the pathway followed by the permeant from the aqueous medium to the
interior of the lipid bilayer, and back out again. A convenient framework for the
computation of permeabilities is provided by the solubility−diffusion model, which
requires knowledge of the underlying free-energy and diffusivity landscapes. Here, we
develop a formalism that includes an explicit description of the orientational motion of the
solute as it diffuses across the membrane. Toward this end, we have generalized a recently
proposed method that reconciles thermodynamics and kinetics in importance-sampling
simulations by means of a Bayesian- inference scheme to reverse-solve the underlying
Smoluchowski equation. Performance of the proposed formalism is examined in the model
cases of a water and an ethanol molecule crossing a fully hydrated lipid bilayer. Our
analysis reveals a conspicuous dependence of the free-energy and rotational diffusivity on
the orientation of ethanol when it lies within the headgroup region of the bilayer.
Specifically, orientations for which the hydroxyl group lies among the polar lipid head
groups, while the ethyl group recedes toward the hydrophobic interior are associated with
free-energy minima 2kBT deep, as well as significantly slower orientational kinetics
compared to the bulk solution or the core of the bilayer. The conspicuous orientational
anisotropy of ethanol at the aqueous interface is suggestive of a complete rotation of the
permeant as it crosses the hydrophobic interior of the membrane.
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2kBT deep, as well as significantly slower orientational kinetics
compared to the bulk solution or the core of the bilayer. The conspicuous orientational
anisotropy of ethanol at the aqueous interface is suggestive of a complete rotation of the
permeant as it crosses the hydrophobic interior of the membrane.
