Influence of the sterol aliphatic side chain on membrane properties: a molecular dynamics study

Abstract

Following a recent experimental investigation of the effect of the length of the alkyl side chain in a series of cholesterol analogues (Angew. Chem., Int. Ed., 2013, 52, 12848-12851), we report here an atomistic molecular dynamics characterization of the behaviour of methyl-branched side chain sterols (iso series) in POPC bilayers. The studied sterols included androstenol (i-C0-sterol) and cholesterol (i-C8-sterol), as well as four other derivatives (i-C5, i-C10, i-C12 and i-C14-sterol). For each sterol, both subtle local effects and more substantial differential alterations of membrane properties along the iso series were investigated. The location and orientation of the tetracyclic ring system is almost identical in all compounds. Among all the studied sterols, cholesterol is the sterol that presents the best matching with the hydrophobic length of POPC acyl chains, whereas longer-chained sterols interdigitate into the opposing membrane leaflet. In accordance with the experimental observations, a maximal ordering effect is observed for intermediate sterol chain length (i-C5, cholesterol, i-C10). Only for these sterols a preferential interaction with the saturated sn-1 chain of POPC (compared to the unsaturated sn-2 chain) was observed, but not for either shorter or longer-chained derivatives. This work highlights the importance of the sterol alkyl chain in the modulation of membrane properties and lateral organization in biological membranes.

The aliphatic chain of cholesterol modulates bilayer interleaflet coupling and domain registration

“…Consistent with a previous AAMD simulation[45] and experiment [46], our simulations indicated that cholesterol’s aliphatic chain length has little effect on phase separation but significantly alters inter-leaflet coupling and domain registration. A major source of this effect is the impact of the aliphatic chain on interaction of lipids across the bilayer mid-plane.…”

“…In summary, we used coarse-grained MD simulations to quantitatively characterize the effect of cholesterol aliphatic chain length on lipid domain stability and dynamics using a three-component model membrane made up of DPPC, DLiPC, and analogs of cholesterol with various aliphatic chain lengths. Consistent with a previous AAMD simulation [45] and experiment [46], our simulations indicated that cholesterol's aliphatic chain length has little effect on phase separation but significantly alters interleaflet coupling and domain registration. A major source of this effect is the impact of the aliphatic chain on interaction of lipids across the bilayer midplane.…”

Diphenylhexatriene membrane probes DPH and TMA-DPH: A comparative molecular dynamics simulation study

“…For the main set of simulations, the topology of the POPC molecule consisted of an united united-atom description for CH, CH 2 , and CH 3 groups, based on the parameters presented by Berger et al [29] for 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC), adapted to take into account the changed parameters for the double bond in the sn-2 acyl chain, as described elsewhere [30,31]. The unitedatom structure and topology of cholesterol were adapted from those of Höltje et al [32] (available for download at the GROMACS webpage, http://www.gromacs.org/@api/deki/files/29/=cholesterol.tgz) by changing the atom types from CH2/CH3 to LP2/LP3 to avoid overcondensation of the bilayer, as previously suggested [33,34] and validated by ourselves in previous studies [35,36]. The starting structures were POPC (128 molecules) or POPC:20 mol% cholesterol (96 POPC:24 cholesterol) bilayers [37], fully hydrated with N40 water molecules per phospholipid.…”

Structure and dynamics of the aliphatic cholesterol side chain in membranes as studied by 2H NMR spectroscopy and molecular dynamics simulation

“…15 This result was also confirmed by recent molecular dynamics (MD) simulations. 16 Sterols bearing an unbranched side chain also promote lipid condensation, but to a lesser extent than the native branched iso-alkyl chain of cholesterol. 17 There is relatively little published work on the structural and dynamical aspects of the aliphatic side chain of cholesterol as opposed to the large body of literature on the order and dynamics of phospholipid chains.…”