Role Of Calcium In Membrane Fusion

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

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

WSU Access

Discipline thesis:degree_discipline

Chemical Engineering and Materials Science

Year dc:date.available

2010

Author dc:creator

• Issa, Zeena Kas

Contributors dc:contributor

• Jeffrey J. Potoff
• Charles W. Manke

• anhydrous
• calcium
• fusion
• lipids
• membrane
• water exclusion
• Chemical Engineering
• Physiology

Repository record dc:identifier

https://digitalcommons.wayne.edu/oa_dissertations/170

OAI identifier oai:identifier

oai:digitalcommons.wayne.edu:oa_dissertations-1169