Jeffrey Comer, Klaus Schulten, and Christophe Chipot.
Calculation of lipid-bilayer permeabilities using an average force.
Journal of Chemical Theory and Computation, 10:554-564, 2014.
COME2014
Calculations of lipid bilayer permeabilities from first principles, using molecular
simulations, would be valuable to rapidly assess the bioavailability of drug candidates, as
well as to decipher, at the atomic level, the mechanisms that underlie the translocation of
permeants. The most common theoretical approach, the solubility-diffusion model,
requires determination of the free energy and the diffusivity as functions of the position of
the permeant. Quantitative predictions of permeability have, however, been stymied by
acute difficulties in calculating the diffusivity, inadequate sampling, and, most insidiously,
systematic biases due to imperfections in the force field, simulation parameters, and the
inherent limitations of the diffusive model. In the present work, we combine importance-
sampling simulations employing an adaptive biasing force with a Bayesian-inference
algorithm to determine the free energy and diffusivity with noteworthy precision and
spatial resolution. In multimicrosecond simulations, we probe the sensitivity of the
permeability estimates to different aspects of the methodology, including the truncation of
short-range interactions, the thermostat, the force-field parameters of the permeant, the
time scale over which the diffusivity is estimated, and the size of the simulated system.
The force-field parameters and time scale dependence of the diffusivities impose the
greatest uncertainties on the permeability estimates. Our simulations highlight the
importance of membrane distortion due to the presence of the permeant, which may be
partially suppressed if the bilayer patch is not large enough. We suggest that
improvements to force fields and more robust kinetic models may be needed to reduce
systematic errors below a factor of two.
Download Full Text
The manuscripts available on our site are provided for your personal
use only and may not be retransmitted or redistributed without written
permissions from the paper's publisher and author. You may not upload any
of this site's material to any public server, on-line service, network, or
bulletin board without prior written permission from the publisher and
author. You may not make copies for any commercial purpose. Reproduction
or storage of materials retrieved from this web site is subject to the
U.S. Copyright Act of 1976, Title 17 U.S.C.
