Understanding the Role of Calcium In Membrane Fusion

Membrane fusion is a localized event which occurs at a sub-millisecond timescale[1] when two distinct lipid bilayers fuse with each other, subsequently opening a channel and allowing the transfer of contents.  This process is a critical step in a variety of cellular functions, including exocytosis, fertilization, and neurotransmitter release[2]. The process of membrane fusion is thermodynamically unfavorable, and several factors are required to overcome the activation energy barrier[3,4]. Ca²⁺ has been identified as one such factor that regulates membrane fusion, although the precise mechanism through which Ca²⁺ triggers membrane fusion remains unclear [5-7]. 

This work is focused on understanding the role of Ca²⁺ in the fusion process at the atomic level.  Using molecular dynamics simulations and a variety of techniques such as adaptive force bias and steered molecular dynamics, the interactions of Ca²⁺, Mg²⁺ and Ba²⁺ with phospholipid bilayers, and the membrane fusion protein snaptotagamin (SYT) are studied.   These simulations show Ca²⁺ has the unique ability to bridge apposed phospholipid head groups, while Mg²⁺ and Ba²⁺ do not.  Potential of mean force calculations are used to show this propensity for Ca²⁺ to bridge opposed bilayers is due to an optimum balance of Ca²⁺-phospholipid and Ca²⁺ water interactions.  The effect of cation binding to phospholipid head groups on the local structure of water and the free energy barriers to phospholipid rearrangement are discussed.

1.  Llinas, R.; Steinberg, I. Z.; Walton, K. Biophys. J. (1981), 33, 323.

2.  Jahn, R.; Sudhoff, T. C. Annu. Rev. Biochem. (1999), 68, 863.

3.  Rand, R. P.; Parsegian, V. A. Biochim. Biophys. Acta (1989), 988, 351.

4.  Kinnunen, P. K. J.; Holopainen, J. M. Biosc. Rep. (2000), 20, 465.

5.  Papahadjopoulos, D.; Poste, Schaeffer, B. E.; Vail, W. J.  Biochim. Biophys. Acta (1974), 352, 10.

6.  Papahadjopoulos, D; Nir, S.; Bizgunes, N. J. Bioenerg. Biomembr. (1990), 22, 157.

7.  Portis, A.; Newton, C.; Pangborn, W.; Papahadjopoulos, D. Biochemistry (1979), 18, 780.