Boundary lipids of the nicotinic acetylcholine receptor: Spontaneous partitioning via coarse-grained molecular dynamics simulation

Publication date: Available online 18 January 2019Source: Biochimica et Biophysica Acta (BBA) - BiomembranesAuthor(s): Liam Sharp, Reza Salari, Grace BranniganAbstractReconstituted nicotinic acetylcholine receptors (nAChRs) exhibit significant gain-of-function upon addition of cholesterol to reconstitution mixtures, and cholesterol affects organization of nAChRs within domain-forming membranes, but whether nAChR partitions to cholesterol-rich liquid-ordered (“raft” or lo) domains or cholesterol-poor liquid-disordered (ldo) domains is unknown. We use coarse-grained molecular dynamics simulations to observe spontaneous interactions of cholesterol, saturated lipids, and polyunsaturated (PUFA) lipids with nAChRs. In binary Dipalmitoylphosphatidylcholine:Cholesterol (DPPC:CHOL) mixtures, both CHOL and DPPC acyl chains were observed spontaneously entering deep “non-annular” cavities in the nAChR TMD, particularly at the subunit interface and the β subunit center, facilitated by the low amino acid density in the cryo-EM structure of nAChR in a native membrane. Cholesterol was highly enriched in the annulus around the TMD, but this effect extended over (at most) 5–10 Å. In domain-forming ternary mixtures containing PUFAs, the presence of a single receptor did not significantly affect the likelihood of domain formation. nAChR partitioned to any cholesterol-poor ldo domain that was present, regardless of whether the ldo or lo domain lipids had PC or PE headgroups. Enrichm...

Source: Biochimica et Biophysica Acta (BBA) Biomembranes - January 20, 2019 Category: Biochemistry Source Type: research