Microsecond Molecular Dynamics Simulations of Lipid Mixing

Molecular
dynamics (MD) simulations of membranes are often hindered by the slow
lateral diffusion of lipids and the limited time scale of MD. In order
to study the dynamics of mixing and characterize the lateral distribution
of lipids in converged mixtures, we report microsecond-long all-atom
MD simulations performed on the special-purpose machine Anton. Two
types of mixed bilayers, POPE:POPG (3:1) and POPC:cholesterol (2:1),
as well as a pure POPC bilayer, were each simulated for up to 2 μs.
These simulations show that POPE:POPG and POPC:cholesterol are each
fully miscible at the simulated conditions, with the final states
of the mixed bilayers similar to a random mixture. By simulating three
POPE:POPG bilayers at different NaCl concentrations (0, 0.15, and
1 M), we also examined the effect of salt concentration on lipid mixing.
While an increase in NaCl concentration is shown to affect the area
per lipid, tail order, and lipid lateral diffusion, the final states
of mixing remain unaltered, which is explained by the largely uniform
increase in Na+ ions around POPE and POPG. Direct measurement
of water permeation reveals that the POPE:POPG bilayer with 1 M NaCl
has reduced water permeability compared with those at zero or low
salt concentration. Our calculations provide a benchmark to estimate
the convergence time scale of all-atom MD simulations of lipid mixing.
Additionally, equilibrated structures of POPE:POPG and POPC:cholesterol,
which are frequently used to mimic bacterial and mammalian membranes,
respectively, can be used as starting points of simulations involving
these membranes.