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Regimes of Complex Lipid Bilayer Phases Induced by Cholesterol Concentration in MD Simulation.

ABSTRACT: Cholesterol is essential to the formation of phase-separated lipid domains in membranes. Lipid domains can exist in different thermodynamic phases depending on the molecular composition and play significant roles in determining structure and function of membrane proteins. We investigate the role of cholesterol in the structure and dynamics of ternary lipid mixtures displaying phase separation using molecular dynamics simulations, employing a physiologically relevant span of cholesterol concentration. We find that cholesterol can induce formation of three regimes of phase behavior: 1) miscible liquid-disordered bulk, 2) phase-separated, domain-registered coexistence of liquid-disordered and liquid-ordered domains, and 3) phase-separated, domain-antiregistered coexistence of liquid-disordered and newly identified nanoscopic gel domains composed of cholesterol threads we name "cholesterolic gel" domains. These findings are validated and discussed in the context of current experimental knowledge, models of cholesterol spatial distributions, and models of ternary lipid-mixture phase separation.

SUBMITTER: Pantelopulos GA

PROVIDER: S-EPMC6289039 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Regimes of Complex Lipid Bilayer Phases Induced by Cholesterol Concentration in MD Simulation.

Pantelopulos George A GA Straub John E JE

Biophysical journal 20181019 11

Cholesterol is essential to the formation of phase-separated lipid domains in membranes. Lipid domains can exist in different thermodynamic phases depending on the molecular composition and play significant roles in determining structure and function of membrane proteins. We investigate the role of cholesterol in the structure and dynamics of ternary lipid mixtures displaying phase separation using molecular dynamics simulations, employing a physiologically relevant span of cholesterol concentra ...[more]

PMID: 30414630

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Project description:Anionic lipids and cholesterols (CHOL) are critical to the function of nicotinic acetylcholine receptors (nAChR). We investigated their interactions with an open- and closed-channel alpha4beta2 nAChR by over 10 ns molecular dynamics simulations in a ternary lipid mixture of 1-palmitoyl-2-oleoyl phosphatidylcholine (POPC), 1-palmitoyl-2-oleoyl phosphatidic acid (POPA), and CHOL with a ratio of 3:1:1 (Haddadian et al., J. Phys. Chem. B 2008, 112, 13981). On average there were 65 and 74 interfacial lipids around the closed- and open-channel alpha4beta2 nAChR, respectively, in the equilibrated simulation systems. In the open-channel system, 42% of the interfacial POPA had acyl chains partially inserted into intra- or intersubunit cavities, as compared to only 7% in the closed-channel alpha4beta2. No CHOL was found in cavities within single subunits, though some CHOL infiltrated into the gaps between subunits. Because of its smaller headgroup, POPA could access some nonannular sites where POPC could not easily reach due to steric exclusion. Furthermore, POPA acted not only as an acceptor for hydrogen bonding (H bonding) as POPC did, but also as a donor through its hydroxyl group for H bonding with the backbone of the protein. The charged headgroup of POPA allowed the lipid to form stable salt bridges with conserved Arg and Lys residues at the interfaces of the transmembrane (TM) and extracellular (EC) or intracellular (IC) domains of the alpha4beta2. A higher number of salt bridges and hydrogen bonds (H bonds) between POPA and the alpha4beta2 nAChR were found in the open system than in the closed system, suggesting a potential role of POPA in the equilibrium between different channel states. Most interfacial POPA molecules showed lower order parameters than the bulk POPA due to the mixed effect of gauche defects, hydrophobic mismatch, and the lipid orientations near the magic angle. These unique properties enable the interfacial POPA to achieve what POPC cannot with regard to specific interactions with the protein, thereby making POPA essential for the function of nAChR.

Project description:Transient receptor potential vanilloid subtype 1 (TRPV1) is a heat-sensitive ion channel also involved in pain sensation, and is the receptor for capsaicin, the active ingredient of hot chili peppers. The recent structures of TRPV1 revealed putative ligand density within the S1 to S4 voltage-sensor-like domain of the protein. However, questions remain regarding the dynamic role of the lipid bilayer in ligand binding to TRPV1. Molecular dynamics simulations were used to explore behavior of capsaicin in a 1-palmitoyl-2-oleoyl phosphatidylcholine bilayer and with the target S1-S4 transmembrane helices of TRPV1. Equilibrium simulations reveal a preferred interfacial localization for capsaicin. We also observed a capsaicin molecule flipping from the extracellular to the intracellular leaflet, and subsequently able to access the intracellular TRPV1 binding site. Calculation of the potential of mean force (i.e., free energy profile) of capsaicin along the bilayer normal confirms that it prefers an interfacial localization. The free energy profile indicates that there is a nontrivial but surmountable barrier to the flipping of capsaicin between opposing leaflets of the bilayer. Molecular dynamics of the S1-S4 transmembrane helices of the TRPV1 in a lipid bilayer confirm that Y511, known to be crucial to capsaicin binding, has a distribution along the bilayer normal similar to that of the aromatic group of capsaicin. Simulations were conducted of the TRPV1 S1-S4 transmembrane helices in the presence of capsaicin placed in the aqueous phase, in the lipid, or docked to the protein. No stable interaction between ligand and protein was seen for simulations initiated with capsaicin in the bilayer. However, interactions were seen between TRPV1 and capsaicin starting from the cytosolic aqueous phase, and capsaicin remained stable in the majority of simulations from the docked pose. We discuss the significance of capsaicin flipping from the extracellular to the intracellular leaflet and mechanisms of binding site access by capsaicin.

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Regimes of Complex Lipid Bilayer Phases Induced by Cholesterol Concentration in MD Simulation.

Publications

Regimes of Complex Lipid Bilayer Phases Induced by Cholesterol Concentration in MD Simulation.

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