indsigt - Computational Biology - # Membrane Deformation and Curvature Sensing by the Influenza A M2 Protein

Conformational Dynamics and Membrane Curvature Sensing of the Influenza A M2 Proton Channel

Q: How do the membrane composition and material properties influence the curvature sensing and localization of different M2 conformations

The membrane composition and material properties play a crucial role in influencing the curvature sensing and localization of different M2 conformations. The lipid composition of the membrane, including the presence of phospholipids, cholesterol, and other lipid species, affects the interactions between M2 and the membrane. For instance, the amphipathic helices of M2 interact differently with lipid headgroups and hydrophobic tails, leading to membrane deformation and curvature generation. The material properties of the membrane, such as bending modulus and compression modulus, determine how the membrane responds to the presence of M2. These properties influence the energy required for membrane deformation and the stability of different membrane shapes induced by M2 conformations. Additionally, the lipid tilt and membrane thickness variations induced by M2 are influenced by the membrane composition and material properties, further impacting the curvature sensing capabilities of M2.

Q: What are the energetic and kinetic barriers that govern the transitions between the different symmetric conformations of M2, and how do these transitions relate to the protein's function during viral egress

The transitions between different symmetric conformations of M2 are governed by both energetic and kinetic barriers. Energetically, the stability of each conformation is influenced by the membrane environment, including the curvature of the membrane and the interactions between M2 and the lipid bilayer. The energetic cost associated with each conformation in different membrane geometries determines the preference of M2 for specific membrane shapes. Kinetically, the transitions between symmetric conformations of M2 depend on the flexibility of the protein structure, the dynamics of the amphipathic helices, and the interactions between different subunits of the M2 tetramer. These transitions are essential for the functional role of M2 during viral egress, as they allow the protein to adapt to different membrane geometries and facilitate membrane scission and viral particle release. The dynamic nature of M2 conformations and their transitions enable the protein to respond to changes in the membrane environment and carry out its role in viral replication.

Q: Could the curvature sensing capabilities of M2 be exploited for the development of novel antiviral therapies targeting viral budding and release

The curvature sensing capabilities of M2 could be potentially exploited for the development of novel antiviral therapies targeting viral budding and release. By understanding how M2 interacts with the membrane, deforms the lipid bilayer, and senses different membrane geometries, researchers can design molecules that specifically target the curvature sensing mechanisms of M2. These molecules could disrupt the ability of M2 to localize to specific membrane regions, inhibit its curvature generation function, or stabilize certain conformations that prevent viral egress. Targeting the curvature sensing capabilities of M2 could lead to the development of therapeutic strategies that interfere with the final stages of the influenza viral life cycle, potentially inhibiting viral replication and spread. Further research into the molecular mechanisms underlying M2 curvature sensing could provide valuable insights for the design of novel antiviral therapies with enhanced efficacy and specificity.

Kernekoncepter

The influenza A M2 protein can adopt different conformations that induce distinct patterns of membrane deformation and curvature sensing, with 2-fold symmetric conformations preferentially stabilized in regions of negative Gaussian curvature.

Resumé

The content explores the conformational dynamics and membrane curvature sensing capabilities of the influenza A M2 proton channel. Key insights include:

Unbiased molecular dynamics (MD) simulations reveal that the amphipathic helix (AH) domains of M2 are highly dynamic, quickly breaking the 4-fold symmetry observed in most structures.
Restrained MD simulations of three different M2 conformations (4-fold symmetric, 2-fold symmetric, and a parallel AH domain model) show that all configurations induce pronounced curvature in the outer (extracellular) leaflet, while the inner (cytoplasmic) leaflet remains relatively flat. This is accompanied by significant lipid tilt in the inner leaflet adjacent to the AH domains.
Continuum elastic membrane modeling using the MD-derived protein-membrane boundary conditions reveals that the 2-fold symmetric conformations are stabilized in regions of negative Gaussian curvature (saddles) by 1-3 kBT compared to a flat membrane, while the 4-fold symmetric structure is not.
The parallel AH domain model is the most favored conformation, being stabilized in saddles with curvatures corresponding to 33 nm radii, which is close to the size of stalled viral buds observed in cells infected by M2 defect mutants.
All M2 conformations are destabilized in the convex spherical caps characteristic of budding virions, consistent with experimental observations that M2 is absent from the spherical cap region.

The work provides atomistic insights into how the conformational dynamics and symmetry of the M2 channel influence its curvature sensing and localization during influenza viral egress.

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Statistik

The membrane is approximately 35 Å thick in the simulations.
The parallel AH domain model is stabilized in saddles with 33 nm radii of curvature.
The membrane distortion energies range from 32 kT for the 4-fold 2L0J structure to 90 kT for the 2-fold 2N70 structure in the 35 Å thick membrane.
Reducing the membrane thickness to 30 Å decreases the distortion energies by about half.

Citater

"The parallel AH domain model is the most favored conformation, being stabilized in saddles with curvatures corresponding to 33 nm radii, which is close to the size of stalled viral buds observed in cells infected by M2 defect mutants."
"All M2 conformations are destabilized in the convex spherical caps characteristic of budding virions, consistent with experimental observations that M2 is absent from the spherical cap region."

Vigtigste indsigter udtrukket fra

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

by Helsell,C. V... kl. www.biorxiv.org 07-05-2022

https://www.biorxiv.org/content/10.1101/2022.07.02.498578v1

Dybere Forespørgsler

How do the membrane composition and material properties influence the curvature sensing and localization of different M2 conformations

The membrane composition and material properties play a crucial role in influencing the curvature sensing and localization of different M2 conformations. The lipid composition of the membrane, including the presence of phospholipids, cholesterol, and other lipid species, affects the interactions between M2 and the membrane. For instance, the amphipathic helices of M2 interact differently with lipid headgroups and hydrophobic tails, leading to membrane deformation and curvature generation. The material properties of the membrane, such as bending modulus and compression modulus, determine how the membrane responds to the presence of M2. These properties influence the energy required for membrane deformation and the stability of different membrane shapes induced by M2 conformations. Additionally, the lipid tilt and membrane thickness variations induced by M2 are influenced by the membrane composition and material properties, further impacting the curvature sensing capabilities of M2.

What are the energetic and kinetic barriers that govern the transitions between the different symmetric conformations of M2, and how do these transitions relate to the protein's function during viral egress

The transitions between different symmetric conformations of M2 are governed by both energetic and kinetic barriers. Energetically, the stability of each conformation is influenced by the membrane environment, including the curvature of the membrane and the interactions between M2 and the lipid bilayer. The energetic cost associated with each conformation in different membrane geometries determines the preference of M2 for specific membrane shapes. Kinetically, the transitions between symmetric conformations of M2 depend on the flexibility of the protein structure, the dynamics of the amphipathic helices, and the interactions between different subunits of the M2 tetramer. These transitions are essential for the functional role of M2 during viral egress, as they allow the protein to adapt to different membrane geometries and facilitate membrane scission and viral particle release. The dynamic nature of M2 conformations and their transitions enable the protein to respond to changes in the membrane environment and carry out its role in viral replication.

Could the curvature sensing capabilities of M2 be exploited for the development of novel antiviral therapies targeting viral budding and release

The curvature sensing capabilities of M2 could be potentially exploited for the development of novel antiviral therapies targeting viral budding and release. By understanding how M2 interacts with the membrane, deforms the lipid bilayer, and senses different membrane geometries, researchers can design molecules that specifically target the curvature sensing mechanisms of M2. These molecules could disrupt the ability of M2 to localize to specific membrane regions, inhibit its curvature generation function, or stabilize certain conformations that prevent viral egress. Targeting the curvature sensing capabilities of M2 could lead to the development of therapeutic strategies that interfere with the final stages of the influenza viral life cycle, potentially inhibiting viral replication and spread. Further research into the molecular mechanisms underlying M2 curvature sensing could provide valuable insights for the design of novel antiviral therapies with enhanced efficacy and specificity.