Effects
of Cholesterol on the Thermodynamics and Kinetics
of Passive Transport of Water through Lipid Membranes
- Publication date
- Publisher
Abstract
While
it has long been known that cholesterol reduces the permeability
of biological membranes to water, the exact mechanism by which cholesterol
influences transmembrane permeation is still unclear. The thermodynamic
and kinetic contributions to the transport of water across mixed DPPC/cholesterol
bilayers of different composition are thus examined by molecular dynamics
simulations. Our analyses show that cholesterol decreases transmembrane
permeability to water mainly by altering the thermodynamics of water
transport. In particular, the free-energy barrier to permeation is
magnified in the dense bilayer interior and the partitioning of water
is significantly lowered. The changes are observed to correlate quantitatively
well with the cholesterol-dependent density and thickness of the bilayers.
In contrast, diffusion coefficients are relatively insensitive to
cholesterol concentration, except in the sparsely populated center
of the bilayer. Diffusion of water in cholesterol-containing bilayers
appears to be related to changes in the free area in the middle of
the bilayer and to the solute cross-sectional area in the denser hydrophobic
regions. Overall, cholesterol is found to have an inhibitory effect
on the permeation of water at all concentrations investigated, although
bilayers containing cholesterol concentrations up to 20 mol % display
a more dramatic dependence on cholesterol content than at higher concentrations.
Our results show that it is possible to quantitatively reproduce the
relative effects of cholesterol on lipid bilayer permeability from
molecular dynamics simulations