Role of calcium in membrane fusion

This project is focused on understanding the role of calcium in membrane fusion at the atomic level. Membrane fusion is an intense area of experimental research, however, direct imaging of the membrane fusion mechanism has not been possible due to transient nature of the fusion process. As an alternative to experiments, molecular dynamics simulations provide a means to investigate the structure and function of complex biological systems with atomic-scale resolution.;Nearly 40 years ago, experiments suggested pure phospholipid vesicles may undergo fusion in the presence of Ca2+. These experiments have shown that Ca2+ interacts strongly with phospholipid membranes, inducing fusion and forming 1:2 complexes of Ca2+/lipid. From these results, it was hypothesized that Ca2+ might induce fusion by reducing the electrostatic repulsion between apposed lipid bilayers. Furthermore, it was proposed that in the initial stages of the fusion process, Ca 2+ formed bridges between apposed lipid bilayers, creating an "anhydrous-complex", expelling water from the lipid head groups. The formation of the anhydrous complex and expulsion of water from the lipid head groups could lead to bilayer destabilization and eventual fusion.;In an effort to understand the role of Ca2+ in fusion of lipid vesicles, molecular dynamics simulations have been performed on closely apposed lipid bilayers composed of DMPC and POPS in the presence of Ca 2+. Of particular interest is the formation of the hypothesized anhydrous complex between apposed phospholipids and Ca2+, and the effect of Ca2+ on the hydration and structure of closely apposed lipid bilayers.;Molecular dynamics simulations show that Ca2+ is capable of bridging apposed bilayers. The bridging brings regions of the bilayers into close contact of ∼3 A. This separation is in close agreement with our preliminary simulation with DMP- in the presence of Ca2+, as well as earlier experimental work. The process of Ca2+ bridging of apposed lipids resulted in significant ordering of the lipid tails and bilayer thinning, consistent with simulations of bilayer dehydration, validating our earlier hypothesis that Ca2+ leads to local dehydration of lipid membranes. Similar calculations performed with Na+ instead of Ca2+ did not exhibit bridging of apposed lipid headgroups, illustrating the unique role of Ca 2+. The simulations presented in this work provide the first evidence from atomistic simulations of the formation of the anhydrous complex hypothesized by experiments.