Why are so many fusogens rod-shaped?

Area of Science:

• Molecular biology
• Biophysics
• Cell biology

Background:

• Molecular fusogens are essential for diverse biological processes, including cellular trafficking, exocytosis, cell-cell fusion, and viral entry.
• Many fusogens, such as SNARE proteins and viral glycoproteins, share a conserved rod-like shape across different superfamilies.

Purpose of the Study:

• To investigate the collective behavior and fusion mechanism of rod-like fusogens using molecular dynamics (MD) simulations.
• To determine if the rod shape is a critical determinant for fusogenic activity and to explore the underlying forces driving membrane fusion.

Main Methods:

• Employed highly coarse-grained molecular dynamics (MD) simulations to model the behavior of rod-like fusogens over long timescales.
• Simulated various fusogen types, including SNARE complexes, class II EFF-1 fusogens, and model rod-shaped complexes, comparing their fusion pathways with globular complexes.

Main Results:

• Rod-like fusogens generated significant entropic forces that cleared fusion sites, induced hemifusion, and ultimately promoted membrane rupture and fusion.
• Increased fusogen density correlated with higher entropic forces and accelerated fusion rates, consistent with experimental observations.
• Simulated rod-shaped complexes, unlike globular ones, consistently drove membrane fusion through similar entropic pathways.

Conclusions:

• The rod shape is an optimal structural feature for generating entropic forces that drive membrane fusion.
• A universal, rod-based membrane fusion mechanism likely underlies the structural convergence observed in diverse eukaryotic and viral fusogens.
• These findings provide insights into the fundamental principles governing membrane fusion and the evolution of fusogenic proteins.