Coarse-grained modeling of annexin A2-induced microdomain formation on a vesicle Article Swipe
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· 2024
· Open Access
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· DOI: https://doi.org/10.1016/j.bpj.2024.06.006
· OA: W4399507261
Annexin A2 (A2)-induced microdomain formation is a key step in biological processes such as Ca<sup>2+</sup>-mediated exocytosis in neuroendocrine cells. In this work, a total of 15 coarse-grained molecular dynamics simulations were performed on vesicle models having a diameter of approximately 250 Å for 15 μs each using the Martini2 force field. Five simulations were performed in the presence of 10 A2, 5 in the presence of A2 but absence of PIP<sub>2</sub>, and 5 simulations in the absence of A2 but presence of PIP<sub>2</sub>. Consistent results were generated among the simulations. A2-induced PIP<sub>2</sub> microdomain formation was observed and shown to occur in three phases: A2-vesicle association, localized A2-induced PIP<sub>2</sub> clustering, and A2 aggregation driving PIP<sub>2</sub> microdomain formation. The relationship between A2 aggregation and PIP<sub>2</sub> microdomain formation was quantitatively described using a novel method which calculated the variance among protein and lipid positions via the Fréchet mean. A large reduction in PIP<sub>2</sub> variance was observed in the presence of A2 but not in its absence. This reduction in PIP<sub>2</sub> variance was proportional to the reduction observed in A2 variance and demonstrates that the observed PIP<sub>2</sub> microdomain formation is dependent upon A2 aggregation. The three-phase model of A2-induced microdomain formation generated in this work will serve as a valuable guide for further experimental studies and the development of novel A2 inhibitors. No microdomain formation was observed in the absence of A2 and minimal A2-membrane interaction was observed in the absence of PIP<sub>2</sub>.
