A continuum membrane model can predict curvature sensing by helix insertion

Fu, Yiben; Zeno, Wade F.; Stachowiak, Jeanne C.; Johnson, Margaret E.

doi:10.1039/d1sm01333e

Cited by 8 publications

(16 citation statements)

References 48 publications

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“…Qualitatively our results can be understood in terms of the MD generated distortion profiles in flat bilayers. The upper leaflet curvatures produced by all configurations favor migration into concave spherical regions and disfavor convex geometries, and the underlying mechanism is a relief of strain or increase in strain depending on the background geometry in a similar spirit to the curvature sensing model proposed by Johnson and coworkers (Fu et al, 2021). Thus, our work corroborates the finding that M2 is not enriched in the convex spherical cap of budding virions.…”

Section: Discussionsupporting

confidence: 88%

Membrane curvature sensing and symmetry breaking of the M2 proton channel from Influenza A

Helsell

Marcoline

Lincoff

et al. 2022

Preprint

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The M2 proton channel aids in the exit of mature influenza viral particles from the host plasma membrane through its ability to stabilize regions of high negative gaussian curvature (NGC) that occur at the neck of budding virions. The channels are homo-tetramers that contain a cytoplasm-facing amphipathic helix (AH) that is necessary and sufficient for NGC generation; however, constructs containing the transmembrane spanning helix, which facilitates tetramerization, exhibit enhanced curvature generation. Here we used all-atom molecular dynamics (MD) simulations to explore the conformational dynamics of M2 channels in lipid bilayers revealing that the AH is dynamic, quickly breaking the 4-fold symmetry observed in most structures. Next, we carried out MD simulations with the protein restrained in 4-fold and 2-fold symmetric conformations to determine the impact on the membrane shape. While each pattern was distinct, all configurations induced pronounced curvature in the outer leaflet with rather subtle lipid tilt, while conversely, the inner leaflets adjacent to the AHs showed minimal curvature and significant lipid tilt. The MD-generated profiles at the protein-membrane interface were then extracted and used as boundary conditions in a continuum elastic membrane model to calculate the membrane bending energy of each conformation embedded in different membrane surfaces characteristic of a budding virus. The calculations show that all three M2 conformations are stabilized in concave spherical caps and destabilized in convex spherical caps, the latter reminiscent of a budding virus. Only C2-broken symmetry conformations are stabilized in NGC surfaces, by 1-3 kBT depending on the AH domain arrangement. The most favored conformation is stabilized in saddles with curvatures corresponding to 33 nm radii. In total, our work provides atomistic insight into the curvature sensing capabilities of M2 channels and how enrichment in the nascent viral particle depends on protein shape and membrane geometry.

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Section: Discussionsupporting

confidence: 88%

Membrane curvature sensing and symmetry breaking of the M2 proton channel from Influenza A

Helsell

Marcoline

Lincoff

et al. 2022

Preprint

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“…Alternatively, this superlinear growth may be driven by cooperative binding of bulk septin to the membrane, which we define as any mechanism where the bound septins facilitate the binding of additional bulk septins to the membrane. One plausible physical model for cooperative binding is that septins locally deform the membrane upon binding, which has been shown in previous computational studies (30,31). These local deformations can increase the probability of forming sufficiently large and stable defects for recruitment of septins from the bulk, leading to a cooperative binding mechanism (6).…”

Section: Assaysmentioning

confidence: 80%

A kinetic basis for curvature sensing by septins

Shi¹,

Cannon

Curtis

et al. 2022

Preprint

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The ability of cells to sense and communicate their shape is central to many of their functions. Much is known about how cells generate complex shapes, yet how they sense and respond to geometric cues remains poorly understood. Septins are GTP-binding proteins that localize to sites of micron-scale membrane curvature. Assembly of septins is a multi-step and multi-scale process but it is unknown how these discrete steps lead to curvature sensing. Here we experimentally examine the time-dependent binding of septins at different curvatures and septin bulk concentrations. These experiments unexpectedly indicated that the curvature preference of septins is not absolute but rather is sensitive to the combinations of membrane curvatures present in a reaction, suggesting there is competition between different curvatures for septin binding. To understand the basis of this result, we developed a kinetic model that connects septins’ self-assembly and curvature sensing properties. Our experimental and modeling results are consistent with curvature-sensitive assembly being driven by cooperative associations of septin oligomers in solution with the bound septins. When combined, the work indicates septin curvature sensing is kinetically determined, sensitive to bulk concentration, and the available membrane curvatures. While much geometry-sensitive assembly in biology is thought to be guided by intrinsic material properties of molecules, this is an important example of how kinetics can drive mesoscale curvature-sensitive assembly of polymers.Significance StatementCells use their membrane curvature to coordinate the activation and spatiotemporal compartmentalization of molecules during key cellular processes. Recent works have identified different proteins that can sense or induce membrane curvature from nano- to micron-scale. Septins are nanoscopic cytoskeletal proteins that preferentially bind to membranes with a narrow range of micron-scale curvatures. Yet the sensing mechanism remains ambiguous. Using a combination of microscopy and kinetic modeling, we show that, unlike most proteins that sense curvature in a single protein scale, curvature sensing in septins is determined kinetically through their multi-step hierarchical assembly on the membrane. This introduces a novel kinetic basis of fidelity, where the same protein can be deployed for differential binding sensitivities in different cellular contexts.

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“…Eq (7) shows that 𝛾 is dependent on the vesicle size 𝑅, the monolayer height ℎ, lipid spontaneous curvature 𝑐 ' , bending modulus 𝜅 and area elasticity modulus 𝜇 ) . The analytical expression of 𝛾 can be found by the general formula for finding the roots to quartic equations [37] or by numerical methods.…”

Section: Spherical Membranementioning

confidence: 99%

“…From this expression, the inner and outer monolayer have the same positive tension, which means they are equally stretched after the lipid flip. For the more general situation, we need to solve Eq (7) numerically for 𝛾, which results in distinct expressions for monolayer equilibrium area (Eq. 4).…”

Section: Spherical Membranementioning

confidence: 99%

“…Continuum surface models that we use here (e.g., Helfrich-Canham-Evans, or HCE [15][16][17]) sit at an intermediate or mesoscale resolution that is computationally much more efficient than MD simulations and more flexible than classical elasticity theory-based continuum models. While they lack the single-lipid resolution of molecular approaches, they can simultaneously measure energetic and structural changes of membranes in response to a range of perturbations at the micron scale [7,18]. By representing the surface in 3D space using points on a 2D triangular mesh, these models can capture realistic membrane shapes with arbitrary topologies [18].…”

Section: Introductionmentioning

confidence: 99%

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Predicting protein curvature sensing across membrane compositions with a bilayer continuum model

Fu,

Johnson,

Beaven

et al. 2024

Preprint

Self Cite

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For a variety of biological processes including endocytosis and signaling, proteins must recruit from the cytoplasm to membranes. Several membrane-binding proteins recognize not only the chemical structure of the membrane lipids but the curvature of the surface, binding more strongly to more highly curved surfaces. One common mechanism of curvature sensing is through the insertion of an amphipathic helix into the outer membrane leaflet. Because lipid composition affects multiple material properties of the membrane including bending rigidity, thickness, lipid tilt, and compressibility, it has not been possible to predict how lipid composition controls protein curvature sensing by helix insertion. Here we develop and apply a two-leaflet continuum membrane model to quantify how such changes to the material properties can favor or disfavor protein curvature sensing by computing energetic and structural changes upon helix insertion, with corroboration againstin vitroexperiments. Our membrane model builds on previous work from our group to explicitly model both monolayers of the bilayer via representation by continuous triangular meshes. To the energy of each monolayer, we introduce a coupling energy that is derived from established energetics of lipid tilt but reformulated into a height term that is methodologically simpler to evaluate. In agreement with molecular dynamics simulations, our model produces a decrease in bilayer height around the site of insertion. We find that increasing membrane height increases curvature sensing. From the protein perspective, deeper or larger insertions also increase curvature sensing. Our experiments of helix insertion by the epsin N-terminal homology (ENTH) on vesicles with varying lipid tail groups show that lipids like DOPC drive stronger curvature sensing than DLPC, despite having the same head-group chemistry, confirming how the material properties of the membrane alter curvature sensing, in excellent agreement with the predictions of our bilayer membrane model. Our model thus quantitatively predicts how changes to membrane composition can alter membrane energetics driven by protein insertion, and can be more broadly extended to characterizing the structure and energetics of protein-driven membrane reshaping by protein assemblies.

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A continuum membrane model can predict curvature sensing by helix insertion

Abstract: Protein domains, such as ENTH (epsin N-terminal homology) and BAR (bin/amphiphysin/rvs), contain amphipathic helices that drive preferential binding to curved membranes.

Cited by 8 publications

References 48 publications

Membrane curvature sensing and symmetry breaking of the M2 proton channel from Influenza A

Membrane curvature sensing and symmetry breaking of the M2 proton channel from Influenza A

A kinetic basis for curvature sensing by septins

Predicting protein curvature sensing across membrane compositions with a bilayer continuum model

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