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A structurally relevant coarse-grained model for cholesterol.

ABSTRACT: Detailed atomistic computer simulations are now widely used to study biological membranes, including increasingly mixed lipid systems that involve, for example, cholesterol, which is a key membrane lipid. Typically, simulations of these systems start from a preassembled bilayer because the timescale on which self-assembly occurs in mixed lipid systems is beyond the practical abilities of fully atomistic simulations. To overcome this limitation and study bilayer self-assembly, coarse-grained models have been developed. Although there are several coarse-grained models for cholesterol reported in the literature, these generally fail to account explicitly for the unique molecular features of cholesterol that relate to its function and role as a membrane lipid. In this work, we propose a new coarse-grained model for cholesterol that retains the molecule's unique features and, as a result, can be used to study crystalline structures of cholesterol. In the development of the model, two levels of coarse-graining are explored and the importance of retaining key molecular features in the coarse-grained model that are relevant to structural properties is investigated.

SUBMITTER: Hadley KR

PROVIDER: S-EPMC2965958 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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A structurally relevant coarse-grained model for cholesterol.

Hadley K R KR McCabe C C

Biophysical journal 20101101 9

Detailed atomistic computer simulations are now widely used to study biological membranes, including increasingly mixed lipid systems that involve, for example, cholesterol, which is a key membrane lipid. Typically, simulations of these systems start from a preassembled bilayer because the timescale on which self-assembly occurs in mixed lipid systems is beyond the practical abilities of fully atomistic simulations. To overcome this limitation and study bilayer self-assembly, coarse-grained mode ...[more]

PMID: 21044587

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Project description:Cholesterol trafficking, which is an essential function in mammalian cells, is intimately connected to molecular-scale interactions through cholesterol modulation of membrane structure and dynamics and interaction with membrane receptors. Since these effects of cholesterol occur on micro- to millisecond timescales, it is essential to develop accurate coarse-grained simulation models that can reach these timescales. Cholesterol has been shown experimentally to thicken the membrane and increase phospholipid tail order between 0-40% cholesterol, above which these effects plateau or slightly decrease. Here, we showed that the published MARTINI coarse-grained force-field for phospholipid (POPC) and cholesterol fails to capture these effects. Using reference atomistic simulations, we systematically modified POPC and cholesterol bonded parameters in MARTINI to improve its performance. We showed that the corrections to pseudo-bond angles between glycerol and the lipid tails and around the oleoyl double bond particle (the "angle-corrected model") slightly improves the agreement of MARTINI with experimentally measured thermal, elastic, and dynamic properties of POPC membranes. The angle-corrected model improves prediction of the thickening and ordering effects up to 40% cholesterol but overestimates these effects at higher cholesterol concentration. In accordance with prior work that showed the cholesterol rough face methyl groups are important for limiting cholesterol self-association, we revised the coarse-grained representation of these methyl groups to better match cholesterol-cholesterol radial distribution functions from atomistic simulations. In addition, by using a finer-grained representation of the branched cholesterol tail than MARTINI, we improved predictions of lipid tail order and bilayer thickness across a wide range of concentrations. Finally, transferability testing shows that a model incorporating our revised parameters into DOPC outperforms other CG models in a DOPC/cholesterol simulation series, which further argues for its efficacy and generalizability. These results argue for the importance of systematic optimization for coarse-graining biologically important molecules like cholesterol with complicated molecular structure.

Dataset Information

A structurally relevant coarse-grained model for cholesterol.

Publications

A structurally relevant coarse-grained model for cholesterol.

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