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

TL;DR

This study uses coarse-grained molecular dynamics simulations to investigate how nicotinic acetylcholine receptors (nAChRs) interact with various lipids, revealing their partitioning behavior and lipid preferences in different membrane environments.

Contribution

It provides new insights into the spontaneous lipid partitioning of nAChRs, especially regarding cholesterol and polyunsaturated fatty acids, using detailed simulation methods.

Findings

Cholesterol and saturated lipids enter nAChR cavities spontaneously.

nAChR prefers cholesterol-poor liquid-disordered domains.

Long n-3 chains like DHA displace cholesterol and occupy embedded sites.

Abstract

Reconstituted 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 $l_o$) domains or cholesterol-poor liquid-disordered ($l_{do}$) 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 $\beta$ 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\AA. 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 $l_{do}$ domain that was present, regardless of whether the $l_{do}$ or $l_o$ domain lipids had PC or PE headgroups. Enrichment of PUFAs among boundary lipids was positively correlated with their propensity for demixing from cholesterol-rich phases. Long $n - 3$ chains (tested here with Docosahexaenoic Acid, DHA) were highly enriched in annular and non-annular embedded sites, partially displacing cholesterol and completely displacing DPPC, and occupying sites even deeper within the bundle. Shorter $n - 6$ chains were far less effective at displacing cholesterol from non-annular sites.