How SNARE proteins generate force to fuse membranes

Area of Science:

• Cell Biology
• Biophysics

Background:

• Membrane fusion, crucial for exocytosis, relies on SNARE proteins, but the fusion mechanism remains unclear.
• Existing models struggle to explain how SNARE complexation energy drives fusion on biologically relevant timescales.

Purpose of the Study:

• To elucidate the biophysical mechanism of SNARE-mediated membrane fusion using advanced computational simulations.
• To investigate the role of entropic forces generated by SNARE complexes in driving fusion.

Main Methods:

• Employed highly coarse-grained molecular dynamics simulations to model SNARE-driven fusion at millisecond timescales.
• Analyzed forces, tensions, and conformational changes in SNARE complexes during the fusion process.

Main Results:

• SNARE complexes generate spontaneous entropic forces (∼8 pN/SNARE) that clear the fusion site and squeeze membranes (∼19 pN/SNARE), initiating hemifusion.
• Multiple SNARE complexes (≥5) generate significant entropic tensions (≥2.5 pN/nm), expanding hemifusion stalks into diaphragms that subsequently rupture for fusion.
• These forces create tensions (∼17-21 pN) in SNARE linker domains, promoting partial unzipping necessary for fusion.

Conclusions:

• Entropic forces, not just complexation energy, are the primary drivers of SNARE-mediated membrane fusion.
• The findings explain how SNAREs catalyze hemifusion and subsequent fusion, clarifying a fundamental cellular process.
• Predicts a dose-dependent relationship between SNARE complex number and fusion speed, consistent with experimental observations.