1 research outputs found
Simulation-Based Approaches for Determining Membrane Permeability of Small Compounds
Predicting the rate of nonfacilitated
permeation of solutes across
lipid bilayers is important to drug design, toxicology, and signaling.
These rates can be estimated using molecular dynamics simulations
combined with the inhomogeneous solubility-diffusion model, which
requires calculation of the potential of mean force and position-dependent
diffusivity of the solute along the transmembrane axis. In this paper,
we assess the efficiency and accuracy of several methods for the calculation
of the permeability of a model DMPC bilayer to urea, benzoic acid,
and codeine. We compare umbrella sampling, replica exchange umbrella
sampling, adaptive biasing force, and multiple-walker adaptive biasing
force for the calculation of the transmembrane PMF. No definitive
advantage for any of these methods in their ability to predict the
membrane permeability coefficient <i>P</i><sub><i>m</i></sub> was found, provided that a sufficiently long equilibration
is performed. For diffusivities, a Bayesian inference method was compared
to a generalized Langevin method, both being sensitive to chosen parameters
and the slow relaxation of membrane defects. Agreement within 1.5
log units of the computed <i>P</i><sub><i>m</i></sub> with experiment is found for all permeants and methods. Remaining
discrepancies can likely be attributed to limitations of the force
field as well as slowly relaxing collective movements within the lipid
environment. Numerical calculations based on model profiles show that <i>P</i><sub><i>m</i></sub> can be reliably estimated
from only a few data points, leading to recommendations for calculating <i>P</i><sub><i>m</i></sub> from simulations