  The nicotinic acetylcholine receptor (nAChR) and other pentameric
ligand-gated ion channels (pLGICs) are native to neuronal membranes with an
unusual lipid composition. While it is well-established that these receptors
can be significantly modulated by lipids, the underlying mechanisms have been
primarily studied in model membranes with only a few lipid species. Here we use
coarse-grained molecular dynamics (MD) simulation to probe specific binding of
lipids in a complex quasi-neuronal membrane. We ran a total of 50 microseconds
of simulations of a single nAChR in a membrane composed of 36 species of
lipids. Competition between multiple lipid species produces a complex
distribution. We find that overall, cholesterol selects for concave
intersubunit sites and PUFAs select for convex M4 sites, while monounsaturated
and saturated lipids are unenriched in the nAChR boundary. In order to
characterize binding to specific sites, we present a novel approach for
calculating a "density-threshold affinity" from continuous density
distributions. We find that affinity for M4 weakens with chain rigidity, which
suggests flexible chains may help relax packing defects caused by the conical
protein shape. For any site, PE headgroups have the strongest affinity of all
phospholipid headgroups, but anionic lipids still yield moderately high
affinities for the M4 sites as expected. We observe cooperative effects between
anionic headgroups and saturated chains at the M4 site in the inner leaflet. We
also analyze affinities for individual anionic headgroups. Combined, these
insights may reconcile several apparently contradictory experiments on the role
of anionic phospholipids in modulating nAChR.
