Continuum descriptions of membranes and their interaction with proteins: Towards chemically accurate models

Argudo, David; Bethel, Neville; Marcoline, Frank V.; Grabe, Michael

doi:10.1016/j.bbamem.2016.02.003

Cited by 44 publications

(54 citation statements)

References 170 publications

(291 reference statements)

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“…S1). The deformation profiles of the upper and lower leaflets using both methods are remarkably similar, as we noted previously (17). The MD simulations confirm that the protein induces a large-amplitude sinusoidal wave along the membrane-protein contact boundary with the greatest distortion centered on the hydrophilic groove.…”

Section: Molecular Simulations Reveal Lipid-interaction Sitessupporting

confidence: 68%

“…For further details on our simulation setup, please refer to our previous work ref. 17 and SI Materials and Methods.…”

Section: Methodsmentioning

confidence: 99%

“…[15][16][17]. Briefly, a physics-based model is used that considers the energy of the protein in the membrane as the sum of three dominant terms:…”

Section: Methodsmentioning

confidence: 99%

“…1B). The energetic cost of the deformation, using standard material properties of 1-palmitoyl-2-oleoyl PC (POPC) bilayers (Table S1) (17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27), is 60 kcal/mol, and the bending energy dominates over the compression and surface tension terms.…”

Section: Tmem16 Induces Large-scale Membrane Deformationsmentioning

confidence: 99%

“…We previously developed a fast, hybrid continuum-atomistic model that treats the protein in atomistic detail, while implicitly representing the membrane using elasticity theory (15)(16)(17). Both our continuum model and MD simulations show that nhTMEM16 generates large-scale membrane deformations around the entire membrane-protein interface, including areas far away from the hydrophilic groove.…”

mentioning

confidence: 99%

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Atomistic insight into lipid translocation by a TMEM16 scramblase

Bethel

Grabe

2016

Proc. Natl. Acad. Sci. U.S.A.

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105

159

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The transmembrane protein 16 (TMEM16) family of membrane proteins includes both lipid scramblases and ion channels involved in olfaction, nociception, and blood coagulation. The crystal structure of the fungal Nectria haematococca TMEM16 (nhTMEM16) scramblase suggested a putative mechanism of lipid transport, whereby polar and charged lipid headgroups move through the low-dielectric environment of the membrane by traversing a hydrophilic groove on the membrane-spanning surface of the protein. Here, we use computational methods to explore the membrane-protein interactions involved in lipid scrambling. Fast, continuum membrane-bending calculations reveal a global pattern of charged and hydrophobic surface residues that bends the membrane in a large-amplitude sinusoidal wave, resulting in bilayer thinning across the hydrophilic groove. Atomic simulations uncover two lipid headgroup-interaction sites flanking the groove. The cytoplasmic site nucleates headgroup-dipole stacking interactions that form a chain of lipid molecules that penetrate into the groove. In two instances, a cytoplasmic lipid interdigitates into this chain, crosses the bilayer, and enters the extracellular leaflet, and the reverse process happens twice as well. Continuum membrane-bending analysis carried out on homology models of mammalian homologs shows that these family members also bend the membrane-even those that lack scramblase activity. Sequence alignments show that the lipid-interaction sites are conserved in many family members but less so in those with reduced scrambling ability. Our analysis provides insight into how large-scale membrane bending and protein chemistry facilitate lipid permeation in the TMEM16 family, and we hypothesize that membrane interactions also affect ion permeation.TMEM16 | lipid scrambling | continuum membrane models | simulation | anoctamin T he compositional asymmetry between the leaflets of the plasma membrane influences the signaling properties of cells. Scramblases are a class of proteins that disrupt membrane asymmetry by facilitating the transfer of phospholipids from one leaflet to the other in an energy-independent manner. These transmembrane proteins play a role in events such as coagulation of the blood and cellular apoptosis by transporting phosphatidylserine (PS) from the inner leaflet to the outer leaflet of the plasma membrane (1). In particular, transmembrane protein 16 (TMEM16) family members have gained recent attention for their role in phospholipid scrambling in platelets and fungi. The TMEM16 family members have diverse functions. For example, TMEM16A and -B are calcium-activated chloride channels, TMEM16F is a nonspecific cation channel and scramblase, and the fungal Aspergillus fumigatus TMEM16 is another dual scramblase/ion channel (2-6).The structure of the Nectria haematococca TMEM16 (nhTMEM16) membrane protein revealed a possible mechanism for phospholipid conduction across the membrane (Fig. 1A) (7). The protein forms a dimer, and each subunit has a hydrophilic groove composed of polar...

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Section: Molecular Simulations Reveal Lipid-interaction Sitessupporting

confidence: 68%

“…For further details on our simulation setup, please refer to our previous work ref. 17 and SI Materials and Methods.…”

Section: Methodsmentioning

confidence: 99%

“…[15][16][17]. Briefly, a physics-based model is used that considers the energy of the protein in the membrane as the sum of three dominant terms:…”

Section: Methodsmentioning

confidence: 99%