How proteins open fusion pores: insights from molecular simulations

Abstract

Fusion proteins can play a versatile and involved role during all stages of the fusion reaction. Their roles go far beyond forcing the opposing membranes into close proximity to drive stalk formation and fusion. Molecular simulations have played a central role in providing a molecular understanding of how fusion proteins actively overcome the free energy barriers of the fusion reaction up to the expansion of the fusion pore. Unexpectedly, molecular simulations have revealed a preference of the biological fusion reaction to proceed through asymmetric pathways resulting in the formation of, e.g., a stalk-hole complex, rim-pore, or vertex pore. Force-field based molecular simulations are now able to directly resolve the minimum free-energy path in protein-mediated fusion as well as quantifying the free energies of formed reaction intermediates. Ongoing developments in Graphics Processing Units (GPUs), free energy calculations, and coarse-grained force-fields will soon gain additional insights into the diverse roles of fusion proteins.

IFITM3 blocks influenza virus entry by sorting lipids and stabilizing hemifusion

“…Measurements of the hemifusion sites (n = 17) (Figure 5A–C) revealed a narrow average outer angle of 63° (SD = 12°) and wide inner viral and cytoplasmic angles of 157° (SD = 11°) and 140° (SD = 13°), respectively. As no significant differences were observed between opposing contact angles, the hemifusion sites were either formed by symmetric expansions or converged into a favorable symmetric geometry (Risselada and Grubmüller, 2021). The average hemifusion diaphragm diameter measured from the phospholipid head groups was 16.5 nm (SD = 5.3 nm, n = 17), consistent with stable hemifusion diaphragms observed in vitro (Chlanda et al, 2016).…”

Enhanced sampling for lipid-protein interactions during membrane dynamics

“…The exocytosis mechanism allows eukaryotic cells to release biological cargo and effectively transport molecules across the plasma membrane (Tomes, 2015;Rizo, 2022). The complexity of the fusion pore as a mechanism to connect intra-cellular organelles and release the contents of vesicles during exocytosis, has made it an interesting object of study both experimentally (Wu et al, 2021;Chang, Chiang and Jackson, 2017;Gucek et al, 2016;Bai et al, 2004) and computationally (Risselada and Grubmüller, 2021;Risselada and Mayer, 2020;. Fig.…”

Enhanced Expansion and Reduced Kiss-and-Run in Fusion Pores Steered by Synaptotagmin-1 C2B Domains

“…[2][3][4] During this unique process, multiple fusion pores form between the acrosomal and plasma membranes, connecting the lumen of the acrosome to the extracellular milieu. [5][6][7] Accurate molecular mechanisms that describe membrane fusion and the formation of the fusion pore have been objects of research among the experimental 8,9 and computational [10][11][12][13] sciences.…”