Coarse-grained simulation studies of gasdermin self-assembly and pore formation

Gasdermins (GSDMs) are pore-forming proteins that trigger pyroptosis, an inflammatory cell death process that plays a crucial role in immunity. Recent experiments and atomistic simulations have shed light on GSDM molecular structure and their conformational transitions when inserting into the membrane to form pores. However, the dynamics of pore assembly remain incompletely understood. In this work, we propose a minimal coarse-grained model of GSDM proteins and run extensive molecular dynamics simulations that bridge the gap between atomistic simulations on a single molecule level and biological length and time scales relevant for membrane pore assembly. We observe supramolecular structures similar to those reported in experiments: rings, slits, and arcs with significantly different pore cross-sections. By informing our model with experimental observations, we show that the dominant regulatory factors for the assembly of pores are closely related to the kinetics of monomer conformational transition from prepore to pore state. When the monomer insertion kinetics is slow (late insertion), protein interaction strength is the key quantity promoting the formation of circular pores (rings), which maximize the pore area and consequentially the transport across the pore. In the case of fast (early) insertion, the ring formation is generally suppressed; we observe a prevalence of slit-like pores that are sub-optimal for transport. Different from the late insertion scenario, the rings are here promoted by increasing the membrane coverage with proteins. Our findings provide a mechanistic basis for understanding and potentially modulating pyroptotic cell death in various physiological and disease contexts.