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Effects of Cholesterol on the Partitioning of a Drug Molecule in Lipid Bilayers.

ABSTRACT: Drug molecules either bind to membrane-bound targets or permeate through cell membranes to reach intracellular targets, and hence, their membrane partition and permeation are of great importance. Here, we studied the effects of cholesterol on the partition of amantadine, an antiflu drug molecule, into 1,2-dimyristoyl-sn-glycero-3-phosphocholine bilayers using molecular dynamics simulations. The membrane partition of amantadine is sensitive to the cholesterol mole fraction (x_chol). In the absence of cholesterol, amantadine is stably bound in membranes, but at x_chol = 32%, it can escape to the aqueous phase, in agreement with recent experiments. The reduced membrane partition of amantadine at a high cholesterol content is mainly due to the perturbation of the bilayer structure and dynamics. Surrounding lipids stabilize amantadine by having their tails wrapped around the drug molecule, and this ability is compromised when cholesterol is present to increase the order in lipid tails. The atomic details on interactions with lipids and perturbations by cholesterol revealed here provide insight into membrane partition and delivery of drug molecules to their targets.

SUBMITTER: Yang Y

PROVIDER: S-EPMC8159892 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Effects of Cholesterol on the Partitioning of a Drug Molecule in Lipid Bilayers.

Yang Yuqin Y Dong Hao H Zhou Huan-Xiang HX

The journal of physical chemistry. B 20210513 20

Drug molecules either bind to membrane-bound targets or permeate through cell membranes to reach intracellular targets, and hence, their membrane partition and permeation are of great importance. Here, we studied the effects of cholesterol on the partition of amantadine, an antiflu drug molecule, into 1,2-dimyristoyl-sn-glycero-3-phosphocholine bilayers using molecular dynamics simulations. The membrane partition of amantadine is sensitive to the cholesterol mole fraction (xch ...[more]

PMID: 33984232

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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

Effects of Cholesterol on the Partitioning of a Drug Molecule in Lipid Bilayers.

Publications

Effects of Cholesterol on the Partitioning of a Drug Molecule in Lipid Bilayers.

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