Cholesterol Packing around Lipids with Saturated and Unsaturated Chains: A Simulation Study

Pandit, Sagar A.; Chiu, See‐Wing; Jakobsson, Eric; Grama, Ananth; Scott, H. L.

doi:10.1021/la8004135

Cited by 103 publications

(139 citation statements)

References 60 publications

Supporting

Mentioning

120

Contrasting

Order By: Relevance

“…It thus appears that cholesterol promotes access of the protein to the membrane. In the absence of PI(4,5)P 2 , cholesterol increased protein affinity to membranes only for the myristoylated protein, consistent with its role to enhance the compatibility of saturated and unsaturated membrane components, as shown in MD simulations (72). In combination, cholesterol and PI(4,5)P 2 increased membrane binding of -myrMA and ϩmyrMA to a similar extent, which indicates that cholesterol particularly facilitates MA access to the phosphatidylinositol headgroup in a way which is independent of the myristate.…”

Section: Discussionmentioning

confidence: 60%

“…The sterol backbone of cholesterol is asymmetrically substituted with methyls that emerge on one face of the ring system, denoted ␣, rendering this face rough on the atomistic scale, whereas the ␤-face, which lacks such substitutions, is smooth (72,73). MD simulations suggested substantial impact of this asymmetry on the binding of cholesterol to saturated (␣-face) and unsaturated (␤-face) lipid chains (72) and the orientation of the sterol backbone within the bilayer (74). In the light of these results, we speculate that cholesterol is essential to mediate insertion of the saturated myristate into the unsaturated DOPC matrix of the bilayer core.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Membrane Binding of HIV-1 Matrix Protein: Dependence on Bilayer Composition and Protein Lipidation

Barros

Heinrich

Datta

et al. 2016

J Virol

View full text Add to dashboard Cite

By assembling in a protein lattice on the host's plasma membrane, the retroviral Gag polyprotein triggers formation of the viral protein/membrane shell. The MA domain of Gag employs multiple signals-electrostatic, hydrophobic, and lipid-specific-to bring the protein to the plasma membrane, thereby complementing protein-protein interactions, located in full-length Gag, in lattice formation. We report the interaction of myristoylated and unmyristoylated HIV-1 Gag MA domains with bilayers composed of purified lipid components to dissect these complex membrane signals and quantify their contributions to the overall interaction. Surface plasmon resonance on well-defined planar membrane models is used to quantify binding affinities and amounts of protein and yields free binding energy contributions, ⌬G, of the various signals. Charge-charge interactions in the absence of the phosphatidylinositide PI(4,5)P 2 attract the protein to acidic membrane surfaces, and myristoylation increases the affinity by a factor of 10; thus, our data do not provide evidence for a PI(4,5)P 2 trigger of myristate exposure. Lipid-specific interactions with PI(4,5)P 2 , the major signal lipid in the inner plasma membrane, increase membrane attraction at a level similar to that of protein lipidation. While cholesterol does not directly engage in interactions, it augments protein affinity strongly by facilitating efficient myristate insertion and PI(4,5)P 2 binding. We thus observe that the isolated MA protein, in the absence of protein-protein interaction conferred by the full-length Gag, binds the membrane with submicromolar affinities. IMPORTANCELike other retroviral species, the Gag polyprotein of HIV-1 contains three major domains: the N-terminal, myristoylated MA domain that targets the protein to the plasma membrane of the host; a central capsid-forming domain; and the C-terminal, genome-binding nucleocapsid domain. These domains act in concert to condense Gag into a membrane-bounded protein lattice that recruits genomic RNA into the virus and forms the shell of a budding immature viral capsid. In binding studies of HIV-1 Gag MA to model membranes with well-controlled lipid composition, we dissect the multiple interactions of the MA domain with its target membrane. This results in a detailed understanding of the thermodynamic aspects that determine membrane association, preferential lipid recruitment to the viral shell, and those aspects of Gag assembly into the membrane-bound protein lattice that are determined by MA. T he polyprotein Gag is an essential component for the reproduction of retroviruses, such as HIV-1, in infected cells. In the production of new viruses, many copies of Gag assemble laterally, either in the cytoplasm or on the plasma membrane (PM) of the host, thus acquiring their lipid envelope as they bud from the cell. Distinct retroviral genera encode Gag proteins which all show a similar domain architecture, with an N-terminal matrix (MA) domain that targets the PM, followed by the capsid (CA) and nucleocapsid ...

show abstract

Section: Discussionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Membrane Binding of HIV-1 Matrix Protein: Dependence on Bilayer Composition and Protein Lipidation

Barros

Heinrich

Datta

et al. 2016

J Virol

View full text Add to dashboard Cite

show abstract

“…The system consisted of 14,661 or 14,668 atoms in total for the C 12 -TPP and SkQR1 ions, respectively. Simulations were performed with the program Gromacs (31) using the G43A1-S3 force field (32) and SPC/E water model (33). The electrostatics were calculated using the particle mesh Ewald method (34), and all bonds were maintained with the LINCS routine (35).…”

Section: Methodsmentioning

confidence: 99%

Derivatives of Rhodamine 19 as Mild Mitochondria-targeted Cationic Uncouplers

Antonenko

Avetisyan

Cherepanov

et al. 2011

Journal of Biological Chemistry

View full text Add to dashboard Cite

A limited decrease in mitochondrial membrane potential can be beneficial for cells, especially under some pathological conditions, suggesting that mild uncouplers (protonophores) causing such an effect are promising candidates for therapeutic uses. The great majority of protonophores are weak acids capable of permeating across membranes in their neutral and anionic forms. In the present study, protonophorous activity of a series of derivatives of cationic rhodamine 19, including dodecylrhodamine (C 12 R1) and its conjugate with plastoquinone (SkQR1), was revealed using a variety of assays. Derivatives of rhodamine B, lacking dissociable protons, showed no protonophorous properties. In planar bilayer lipid membranes, separating two compartments differing in pH, diffusion potential of H ؉ ions was generated in the presence of C 12 R1 and SkQR1. These compounds induced pH equilibration in liposomes loaded with the pH probe pyranine. C 12 R1 and SkQR1 partially stimulated respiration of rat liver mitochondria in State 4 and decreased their membrane potential. Also, C 12 R1 partially stimulated respiration of yeast cells but, unlike the anionic protonophore FCCP, did not suppress their growth. Loss of function of mitochondrial DNA in yeast (grande-petite transformation) is known to cause a major decrease in the mitochondrial membrane potential. We found that petite yeast cells are relatively more sensitive to the anionic uncouplers than to C 12 R1 compared with grande cells. Together, our data suggest that rhodamine 19-based cationic protonophores are self-limiting; their uncoupling activity is maximal at high membrane potential, but the activity decreases membrane potentials, which causes partial efflux of the uncouplers from mitochondria and, hence, prevents further membrane potential decrease.Transport of electrons along the mitochondrial respiratory chain is accompanied by the formation of an electrochemical gradient of hydrogen ions (⌬ H ϩ) 3 at the inner mitochondrial membrane. ⌬ H ϩ is used for ATP production and other energyconsuming processes. However, high values of ⌬ H ϩ can increase the production of dangerous reactive oxygen species (ROS) (1, 2). Although mitochondria are able to control ⌬ H ϩ by adjusting the activity of natural uncoupling mechanisms (i.e. free fatty acids, anion carriers, and uncoupling proteins) (3), there is considerable interest in finding pharmacological agents to increase mitochondrial proton leak and, as a consequence, to prevent obesity and to decrease ROS production (4 -7).Uncouplers, or protonophores, are small organic compounds capable of carrying hydrogen ions across artificial and biological membranes. The strategy of "mild uncoupling" (2) relies on the fact that partial decrease in ⌬ H ϩ can be beneficial for cells especially under some pathological conditions, suggesting that uncouplers are good candidates for therapeutic uses. Apparently, such applications are hindered by high toxicity, as in the case of 2,4-dinitrophenol (DNP), which was temporarily used at the beg...

show abstract

“…The condensing effect of CHOL was investigated for two monounsaturated phospholipid systems with 40 mol % CHOL and without CHOL composed of short-chain 14:1(n-5)cis/14:1(n-5)cis PC and long-chain 22:1(n-9)cis/22:1(n-9)cis PC 220 , for 18:1(n-9)cis/18:1(n-9)cis PC bilayer studied by MD using different force fields 61 , for 16:0/16:0 PC, 16:0/18:1(n-9)cis PC, and 18:1(n-9)cis/18:1(n-9)cis PC bilayers with varying concentrations of CHOL (10,20,25, and 33 mol %) 137 , for a system of 16:0/18:1(n-9)cis PC -CHOL (40 mol %) 132 , for a mixture of 18:0-SM (∼ 15 mol %), 18:1(n-9)cis/18:1(n-9)cis PC (∼ 78 mol %), and CHOL (∼ 7 mol %) 121 122 , for 18:0-SM -CHOL (∼ 46 mol %) 216 , 16:0/18:1(n-9)cis PC -16:0/SM 126 , for 18:0-SM -CHOL (0, 22, and 50 mol %) bilayer systems and 15:0/18:0 PC -CHOL bilayer (22 mol %) 219 , for pure bilayers of 18:0-SM, 18:1(n-9)cis-SM, and 16:0/18:1(n-9)cis PC and those with 34 mol % CHOL 131 , for bilayers of 18:0-SM and 16:0/18:1(n-9)cis PC with low content of CHOL 139 .…”

Section: Effect Of Cholesterol On Bond Order Parameters Of Phospholipidsmentioning

confidence: 99%

“…They are assessable experimentally by the NMR technique. The bond ordering in various phospholipid and phospholipid/CHOL bilayers have been studied repeatedly within recent years by computer simulation methods 56,57,61,81,93,109,115,121,122,[126][127][128][129][130][131][132]134,136,137,139,141,143,[213][214][215][216][217][218][219][220][221] .…”

Section: Effect Of Cholesterol On Bond Order Parameters Of Phospholipidsmentioning

confidence: 99%

Recent development in computer simulations of lipid bilayers

2011

View full text Add to dashboard Cite

Rapid development of computer power during the last decade has made molecular simulations of lipid bilayers feasible for many research groups, which, together with the growing general interest in investigations of these very important biological systems has lead to tremendous increase of the number of research on the computational modeling of lipid bilayers. In this review, we give account of the recent progress in computer simulations of lipid bilayers covering mainly the period of the last 5 years, and covering several selected subjects: development of the force fields for lipid bilayer simulations, studies of the role of lipid unsaturation, the effect of cholesterol and other inclusions on properties of the bilayer, and use of coarse-grained models.

show abstract

Cholesterol Packing around Lipids with Saturated and Unsaturated Chains: A Simulation Study

Cited by 103 publications

References 60 publications

Membrane Binding of HIV-1 Matrix Protein: Dependence on Bilayer Composition and Protein Lipidation

Membrane Binding of HIV-1 Matrix Protein: Dependence on Bilayer Composition and Protein Lipidation

Derivatives of Rhodamine 19 as Mild Mitochondria-targeted Cationic Uncouplers

Recent development in computer simulations of lipid bilayers

Contact Info

Product

Resources

About