Sublytic gasdermin-D pores captured in atomistic molecular simulations

Area of Science:

• Cellular biology
• Biophysics
• Computational biology

Background:

• Gasdermin-D (GSDMD) is a key mediator of pyroptosis, a pro-inflammatory programmed cell death pathway.
• GSDMD activation involves caspase-mediated cleavage, releasing the N-terminal domain (GSDMD^NT) that drives membrane permeabilization.

Purpose of the Study:

• To elucidate the molecular mechanisms of GSDMD^NT-induced plasma membrane pore formation using atomistic molecular dynamics simulations.
• To investigate the interactions of GSDMD^NT with membrane lipids and the structural transitions during pore assembly.

Main Methods:

• Atomistic molecular dynamics simulations of GSDMD^NT monomers, oligomers, and rings.
• Modeling of an asymmetric plasma membrane mimetic containing key phospholipids like PI(4,5)P₂ and PS.
• Analysis of GSDMD^NT-lipid interactions, conformational changes, and pore formation dynamics.

Main Results:

• Identified specific binding motifs of GSDMD^NT with PI(4,5)P₂ and PS headgroups, dependent on GSDMD^NT conformation.
• Demonstrated that GSDMD^NT oligomers stabilize membrane pores through inter-monomer lipid binding.
• Observed pore formation from GSDMD^NT arcs and the generation of slit or closed ring pores from high-order oligomers under membrane line tension.

Conclusions:

• GSDMD^NT oligomers directly induce stable, ion-conducting membrane pores.
• Sublytic pore formation explains nonselective ion flux in early pyroptosis.
• Simulations provide atomic-level insights into GSDMD-mediated membrane damage and pyroptosis progression.