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Electron crystallography; lipd bilayer; atomistic simulations
Abstract:
Lipid–protein interactions play pivotal roles in biological membranes.
Electron crystallographic studies of the lens-specific water
channel aquaporin-0 (AQP0) revealed atomistic views of such
interactions, by providing high-resolution structures of annular lipids
surrounding AQP0. It remained unclear, however, whether
these lipid structures are representative of the positions of unconstrained
lipids surrounding an individual protein, and what molecular
determinants define the lipid positions around AQP0. We
addressed these questions by using molecular dynamics simulations
and crystallographic refinement, and calculated time-averaged
densities of dimyristoyl-phosphatidylcholine lipids around
AQP0. Our simulations demonstrate that, although the experimentally
determined crystallographic lipid positions are constrained by
the crystal packing, they appropriately describe the behavior of unconstrained
lipids around an individual AQP0 tetramer, and thus
likely represent physiologically relevant lipid positions.While the
acyl chains were well localized, the lipid head groups were not.
Furthermore, in silico mutations showed that electrostatic inter
actions do not play a major role attracting these phospholipids towards
AQP0. Instead, the mobility of the protein crucially modulates
the lipid localization and explains the difference in lipid
density between extracellular and cytoplasmic leaflets. Moreover,
our simulations support a general mechanism in which membrane
proteins laterally diffuse accompanied by several layers of localized
lipids, with the positions of the annular lipids being influenced the
most by the protein surface. We conclude that the acyl chains
rather than the head groups define the positions of dimyristoylphosphatidylcholine
lipids around AQP0. Lipid localization is largely
determined by the mobility of the protein surface, whereas
hydrogen bonds play an important but secondary role.
