Molecular Modeling of Lipid Membrane Curvature Induction by a Peptide: More than Simply Shape

Sodt, Alexander J.; Pastor, Richard W.

doi:10.1016/j.bpj.2014.02.037

Cited by 68 publications

(70 citation statements)

References 60 publications

(64 reference statements)

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“…These changes are consistent with a recent investigation of a different peptide inserted in a lamellar bilayer (12). In the outer-leaflet headgroups, the pressure is less negative than in the inner leaflet headgroup region (thus reversing the trend seen in the pure vesicle).…”

supporting

confidence: 92%

“…Using coarse-grained MD simulations, we recapitulated this finding, showing that aSyn induces positive mean curvature fields (~30-40 nm) in flat bilayers. This curvature-effect stems from the protein's specific insertion depth (1-4 Å beneath the headgroup phosphates (6,9,10)), a highly specific location that has been predicted to induce positive curvature (11,12). Of note, an amphipathic segment of apolipoprotein A-I has been shown to partition to the same approximate location (13) prebound at the experimental lipid-protein ratio (200:1) (3).…”

mentioning

confidence: 99%

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α-Synuclein Reduces Tension and Increases Undulations in Simulations of Small Unilamellar Vesicles

Braun

Sachs

2015

Biophysical Journal

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Using coarse-grained molecular dynamics simulations we have explored the effect of a-Synuclein (aSyn) on the structural and mechanical properties of small unilamellar vesicles in the fluid-phase. The study is motivated by observations that a high density of membrane-bound aSyn inhibits the fusion of synthetic small unilamellar vesicles. By combining three-dimensional pressure tensor calculations with our recently developed spherical harmonics fluctuation analysis approach, we show a reduction in membrane surface tension and increased membrane undulations when aSyn is bound to the vesicle's outer leaflet at a 200:1 L/P. The protein effects these changes by decreasing the negative pressure in the headgroup region of the outer leaflet and increasing the positive pressure throughout the hydrocarbon core.Received for publication 2 December 2014 and in final form 10 March 2015.*Correspondence: jnsachs@umn.edu Multiple in vivo studies have shown that membrane-bound a-Synuclein (aSyn), an amphipathic a-helix that associates with synaptic vesicles (SVs) (1), can disrupt SV trafficking (2). A recent in vitro study showed that aSyn inhibits fusion of small unilamellar vesicles (SUVs) (3), whose size closely matches that of SVs (~30-40 nm diameter). This effect was seen both in DPPC SUVs in the gelphase and, importantly, in a more physiologically relevant quaternary lipid mixture in the fluid-phase (DOPC/DOPE/ SM/Chol). This mixture is highly fusogenic and was originally conceived to closely mimic the lipid composition of synaptic vesicles (4). DeWitt and Rhoades (5) have recently shown that aSyn inhibits SNARE-mediated fusion of fluid-phase SUVs without interacting directly with those proteins.Collectively, these findings have led to the hypothesis that aSyn inhibits fusion through direct alteration of the lipid bilayer's physical properties (2,3,5-7). Once biophysical mechanisms for these inhibitory effects are understood, the impact is expected to extend to other proteins with similar amphipathic characteristics. For example, apolipoprotein A-I, a related, but larger membrane binding protein that shares aSyn's amphipathic 11-mer repeat sequence, was also shown to inhibit vesicle fusion. On the other hand, a short (but still amphipathic) segment of aSyn has no inhibitory effect (3). Exactly what bestows aSyn with its antifusogenic activity, be it sequence-specific or a more generic feature of all amphipathic helices, remains unknown.Because of their small size, SUVs are under high curvature stress, imparting an intrinsic driving force for fusion. In the case of gel-phase SUVs, thermodynamic measurements prompted the hypothesis that aSyn anneals defect zones in the lipid matrix, thus inhibiting SUV fusion by relieving curvature stress (3,7). However, no direct experimental measurements to test this hypothesis have yet been made. Our early molecular dynamics (MD) simulations of aSyn bound to SDS micelles were consistent with this idea, showing that the protein relaxes the highly curved spherical micelle into an ell...

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supporting

confidence: 92%

mentioning

confidence: 99%

α-Synuclein Reduces Tension and Increases Undulations in Simulations of Small Unilamellar Vesicles

Braun

Sachs

2015

Biophysical Journal

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“…Therefore, lipid-packing defects can be viewed as a molecular description of interfacial membrane stresses used in continuum membrane physics. However, the advantage of describing and quantifying the contributions of lipid shape and membrane curvature at an atomic scale is to better acknowledge the complexity and variety of lipid membrane interfaces 46 .…”

Section: Discussionmentioning

confidence: 99%

A sub-nanometre view of how membrane curvature and composition modulate lipid packing and protein recruitment

et al. 2014

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Two parameters of biological membranes, curvature and lipid composition, direct the recruitment of many peripheral proteins to cellular organelles. Although these traits are often studied independently, it is their combination that generates the unique interfacial properties of cellular membranes. Here, we use a combination of in vivo, in vitro and in silico approaches to provide a comprehensive map of how these parameters modulate membrane adhesive properties. The correlation between the membrane partitioning of model amphipathic helices and the distribution of lipid-packing defects in membranes of different shape and composition explains how macroscopic membrane properties modulate protein recruitment by changing the molecular topography of the membrane interfacial region. Furthermore, our results suggest that the range of conditions that can be obtained in a cellular context is remarkably large because lipid composition and curvature have, under most circumstances, cumulative effects.

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“…The lateral pressure of a bilayer is related to the surface tension, the curvature, and the behavior of membrane proteins (73)(74)(75). Generally, a membrane pressure profile along the z axis is not uniform because of the large interfacial free energy over membrane headgroups and water molecules; positive lateral pressure arises from repulsive interactions and negative pressure indicates attractive interactions.…”

Section: Distinctive Characteristics Of the Lateral Pressure Profilementioning

confidence: 99%

“…0 (75,76), where k c (> 0) is the bending modulus and R À1 0 is the spontaneous curvature of the leaflet. The calculated F 0 for AB-B is 0.164 kcal/(mol,Å ), implying that AB-B lipid A would induce negative curvature to the leaflet where it resides (if the constraints of the periodic boundary conditions are relaxed).…”

Section: Distinctive Characteristics Of the Lateral Pressure Profilementioning

confidence: 99%

Bilayer Properties of Lipid A from Various Gram-Negative Bacteria

Kim

Patel

Park

et al. 2016

Biophysical Journal

132

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Lipid A is the lipid anchor of a lipopolysaccharide in the outer leaflet of the outer membrane of Gram-negative bacteria. In general, lipid A consists of two phosphorylated N-acetyl glucosamine and several acyl chains that are directly linked to the two sugars. Depending on the bacterial species and environments, the acyl chain number and length vary, and lipid A can be chemically modified with phosphoethanolamine, aminoarabinose, or glycine residues, which are key to bacterial pathogenesis. In this work, homogeneous lipid bilayers of 21 distinct lipid A types from 12 bacterial species are modeled and simulated to investigate the differences and similarities of their membrane properties. In addition, different neutralizing ion types (Ca 2þ , K þ , and Na þ ) are considered to examine the ion's influence on the membrane properties. The trajectory analysis shows that (1) the area per lipid is mostly correlated to the acyl chain number, and the area per lipid increases as a function of the acyl chain number; (2) the hydrophobic thickness is mainly determined by the average acyl chain length with slight dependence on the acyl chain number, and the hydrophobic thickness generally increases with the average acyl chain length; (3) a good correlation is observed among the area per lipid, hydrophobic thickness, and acyl chain order; and (4) although the influence of neutralizing ion types on the area per lipid and hydrophobic thickness is minimal, Ca 2þ stays longer on the membrane surface than K þ or Na þ , consequently leading to lower lateral diffusion and a higher compressibility modulus, which agrees well with available experiments.

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Molecular Modeling of Lipid Membrane Curvature Induction by a Peptide: More than Simply Shape

Cited by 68 publications

References 60 publications

α-Synuclein Reduces Tension and Increases Undulations in Simulations of Small Unilamellar Vesicles

α-Synuclein Reduces Tension and Increases Undulations in Simulations of Small Unilamellar Vesicles

A sub-nanometre view of how membrane curvature and composition modulate lipid packing and protein recruitment

Bilayer Properties of Lipid A from Various Gram-Negative Bacteria

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