Cholesterol Flip-Flop in Heterogeneous Membranes

Cholesterol
is the most abundant molecule in the plasma membrane
of mammals. Its distribution across the two membrane leaflets is critical
for understanding how cells work. Cholesterol trans-bilayer motion
(flip-flop) is a key process influencing its distribution in membranes.
Despite extensive investigations, the rate of cholesterol flip-flop
and its dependence on the lateral heterogeneity of membranes remain
uncertain. In this work, we used atomistic molecular dynamics simulations
to sample spontaneous cholesterol flip-flop events in a DPPC:DOPC:cholesterol
mixture with heterogeneous lateral distribution of lipids. In addition
to an overall flip-flop rate at the time scale of sub-milliseconds,
we identified a significant impact of local environment on flip-flop
rate. We discuss the atomistic details of the flip-flop events observed
in our simulations.