Caveolin-membrane

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Last Updated: Wednesday, 21 August 2013 11:23

Cholesterol Modulates the Structure, Binding Modes and Energetics of Caveolin-Membrane Interactions. Durba Sengupta, J. Phys. Chem. B, Just Accepted Manuscript, 2012. DOI: 10.1021/jp3077886

Caveolin-1 (cav-1) is an important membrane protein that plays a vital role in cellular signalling and trafficking by organising membrane domains. The peptide interacts with cholesterol-rich membranes and induces large morphological changes in them forming microdomains such as caveolae. Here, we use coarse-grained molecular dynamics simulations to study the interaction of cav-1 peptides with several model bilayer systems mimicking biological scenarios, such as cholesterol-rich domains, cholesterol-depleted domains and unsaturated lipid domains. We show that cholesterol modulates the depth as well as orientation of cav-1 binding to membranes. Furthermore, the presence of cholesterol establishes more open-conformations of cav-1, and we speculate that the binding modes and open-conformations could be responsible for inducing morphological changes in the bilayer. We also calculated the partitioning free energy to difference bilayers and show that binding to cholesterol-rich bilayers is more favorable than cholesterol depleted bilayers and the binding to unsaturated bilayers is the least favorable. Binding to cholesterol-rich bilayers also changes the pressure profile of the bilayer to which it is bound and thereby affects the local spontaneous curvature. Our results highlight molecular details of protein-lipid interplay and provide new insights into the effects of cav-1 in tuning the morphology of cholesterol rich membranes.

 

 

bilayer permeability

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Last Updated: Monday, 19 August 2013 14:42

"Coarse-Grained Molecular Dynamics Study of Permeability Enhancement in DPPC Bilayers by Incorporation of Lysolipid" by N.D. Winter and G.C. Schatz J. Phys. Chem. B, 2010, 114, 5053–5060.

The enhanced permeability of flat lipid bilayer membranes at their gel to liquid-crystalline (LC) phase transition has been explored using coarse-grained molecular dynamics. The phase transition temperature, Tm, is deduced by monitoring the area per lipid, the lipid lateral diffusion constant, and the lipid−lipid radial distribution function. We find that a peak in the permeability coincides with the phase transition from the gel to LC state when lysolipid is present. This peak in permeability correlates with a jump in the area per lipid near the same temperature as well as increased fluctuations in the lipid bilayer free volume. At temperatures above Tm, the permeability is only slightly dependent on the amount of lysolipid present. The increased free volume due to the “missing tail” of the lysolipid is partially compensated for by a decrease in area per lipid as the amount of lysolipid increases. We also found that in the coarse-grained model a small amount (≤15 mol %) of lysolipid stabilizes the gel phase and increases the phase transition temperature, while a larger amount of lysolipid (20 mol %) reduces Tm back to that for pure DPPC, and bilayers consisting of ≥30 mol % lysolipid did not form a gel phase but still exhibited a peak in permeability near Tm for pure DPPC.

PC/Chol phase behavior

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Last Updated: Wednesday, 21 August 2013 11:44

Qaiser Waheed, Richard Tjörnhammar, Olle Edholm. Phase Transitions in Coarse-Grained Lipid Bilayers Containing Cholesterol by Molecular Dynamics Simulations. Biophys. J. 103, 2125-2133, 2012.

Coarse-grained simulations of model membranes containing mixtures of phospholipid and cholesterol molecules at different concentrations and temperatures have been performed. A random mixing without tendencies for segregation or formation of domains was observed on spatial scales corresponding to a few thousand lipids and timescales up to several microseconds. The gel-to-liquid crystalline phase transition is successively weakened with increasing amounts of cholesterol without disappearing completely even at a concentration of cholesterol as high as 60%. The phase transition temperature increases slightly depending on the cholesterol concentration. The gel phase system undergoes a transition with increasing amounts of cholesterol from a solid-ordered phase into a liquid-ordered one. In the solid phase, the amplitude of the oscillations in the radial distribution function decays algebraically with a prefactor that goes to zero at the solid-liquid transition.

Transmembrane helix alignment

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Last Updated: Monday, 19 August 2013 14:42

"Changes in Transmembrane Helix Alignment by Arginine Residues Revealed by Solid-State NMR Experiments and Coarse-Grained MD Simulations" by V.V. Vostrikov, B.A. Hall, D.V. Greathouse, R.E. Koeppe, II and M.S.P. Sansom. J. Am. Chem. Soc., 2010, 132, 5803–5811

Independent experimental and computational approaches show agreement concerning arginine/membrane interactions when a single arginine is introduced at selected positions within the membrane-spanning region of acetyl-GGALW5LALALAL12AL14ALALW19LAGA-ethanolamide, designated GWALP23. Peptide sequence isomers having Arg in position 12 or position 14 display markedly different behaviors, as deduced by both solid-state NMR experiments and coarse-grained molecular dynamics (CG-MD) simulations. With respect to the membrane normal of DOPC or DPPC lipid bilayer membranes, GWALP23-R14 shows one major state whose apparent average tilt is 10° greater than that of GWALP23. The presence of R14 furthermore induces bilayer thinning and peptide displacement to “lift” the charged guanidinium toward the bilayer surface. By contrast, GWALP23-R12 exhibits multiple states that are in slow exchange on the NMR time scale, with CG-MD simulations indicating two distinct positions with different screw rotation angles in the membrane, along with an increased tendency to exit the lipid bilayer.

Proteins in dynamic complexes

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Last Updated: Monday, 19 August 2013 14:42

"Membrane Proteins Diffuse as Dynamic Complexes with Lipids" by P.S. Niemela, M.S. Miettinen, L. Monticelli, H. Hammaren, P. Bjelkmar, T. Murtola, E. Lindahl and I. Vattulainen. J. Am. Chem. Soc., 2010, 132, 7574–7575.

We describe how membrane proteins diffuse laterally in the membrane plane together with the lipids surrounding them. We find a number of intriguing phenomena. The lateral displacements of the protein and the lipids are strongly correlated, as the protein and the neighboring lipids form a dynamical protein−lipid complex, consisting of 50−100 lipids. The diffusion of the lipids in the complex is much slower compared to the rest of the lipids. We also find a strong directional correlation between the movements of the protein and the lipids in its vicinity. The results imply that in crowded membrane environments there are no “free” lipids, as they are all influenced by the protein structure and dynamics. Our results indicate that, in studies of cell membranes, protein and lipid dynamics have to be considered together.

Chemoreceptor oligomers

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Last Updated: Wednesday, 21 August 2013 11:23

 

 

Hall BA, Armitage JP, Sansom MSP Mechanism of Bacterial Signal Transduction Revealed by Molecular Dynamics of Tsr Dimers and Trimers of Dimers in Lipid Vesicles. PLoS Comput Biol 8(9): e1002685, 2012.

Bacterial chemoreceptors provide an important model for understanding signalling processes. In the serine receptor Tsr from E. coli, a binding event in the periplasmic domain of the receptor dimer causes a shift in a single transmembrane helix of roughly 0.15 nm towards the cytoplasm. This small change is propagated through the ~22 nm length of the receptor, causing downstream inhibition of the kinase CheA. This requires interactions within a trimer of receptor dimers. Additionally, the signal is amplified across a 53,000 nm2 array of chemoreceptor proteins, including ~5,200 receptor trimers-of-dimers, at the cell pole. Despite a wealth of experimental data on the system, including high resolution structures of individual domains and extensive mutagenesis data, it remains uncertain how information is communicated across the receptor from the binding event to the downstream effectors. We present a molecular model of the entire Tsr dimer, and examine its behaviour using coarse-grained molecular dynamics and elastic network modelling. We observe a large bending in dimer models between the linker domain HAMP and coiled-coil domains, which is supported by experimental data. Models of the trimer of dimers, built from the dimer models, are more constrained and likely represent the signalling state. Simulations of the models in a 70 nm diameter vesicle with a biologically realistic lipid mixture reveal specific lipid interactions and oligomerisation of the trimer of dimers. The results indicate a mechanism whereby small motions of a single helix can be amplified through HAMP domain packing, to initiate large changes in the whole receptor structure.