(721f) 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.

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