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Results from a field-theoretic approach to membrane fusion

Results from a field-theoretic approach to membrane fusion. Michael Schick Department of Physics University of Washington. à mon cher maître. à mon cher maître. à mon cher maître. Maurice Ravel. Synaptic Vesicles. They are small R~15-25 nm cf bilayer thickness t~4nm

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Results from a field-theoretic approach to membrane fusion

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  1. Results from a field-theoreticapproach to membrane fusion Michael Schick Department of Physics University of Washington

  2. à mon cher maître

  3. à mon cher maître

  4. à mon cher maître Maurice Ravel

  5. Synaptic Vesicles They are small R~15-25 nm cf bilayer thickness t~4nm They dock: nothing happens They are triggered: fuse rapidly Fusion on demand

  6. Synaptic vesicles in C. Elegans J.L. Bessereau: www.biologie.ens.fr

  7. Questions • Why does fusion occur and how? • What are free energy barriers to fusion? • What factors promote fusion?

  8. Theoretical Procedure Consider fusion of vesicles of block copolymer: universality

  9. Theoretical Procedure Consider fusion of vesicles of block copolymer: universality Polymers->Random walk->Diffusion Eq.-> Quantum Mech.

  10. Theoretical Procedure Consider fusion of vesicles of block copolymer: universality Polymers->Random walk->Diffusion Eq.-> Quantum Mech. SCFT of interacting polymers-> Hartree Theory Advantages: microscopic model->architecture calculation of free energies

  11. WHY DOES FUSION OCCUR? Bringing bilayers together removes water-> free energy per area increases-> bilayers are under tension

  12. WHY DOES FUSION OCCUR? Bringing bilayers together removes water-> free energy per area increases-> bilayers are under tension Fusion eliminates area -> reduces the free energy Fusion is one possible response to induced tension Lysis (rupture) is another

  13. HOW DOES FUSION OCCUR? one commonly accepted mechanism

  14. Profiles obtained by the theory Kozlov and Markin 1983

  15. WHAT ARE THE FREE ENERGY BARRIERS TO FUSION?

  16. WHAT ARE THE FREE ENERGY BARRIERS TO FUSION? Consider the fusion of two bilayers One component only A lamellar former

  17. Profiles obtained by the theory Kozlov and Markin 1983

  18. 1 bilayer =4.3 Rg One component, f = 0.4 (DOPC), g/g0 = 0.2, equilibrium H, stalk

  19. One component, f = 0.4, g/g0 = 0.2, equilibrium H, stalk

  20. One component, f = 0.4, g/g0 = 0.2, equilibrium H, stalk

  21. One component, f = 0.4, g/g0 = 0.2, equilibrium H, stalk

  22. One component, f = 0.4, g/g0 = 0.2, equilibrium H, pore

  23. One component, f = 0.4, g/g0 = 0.2, equilibrium H, stalk & pore

  24. In lipids, barrier would be 50 kT ! One component, f = 0.4, g/g0 = 0.2, equilibrium H, stalk & pore

  25. WHAT FACTORS AFFECT FUSION?

  26. Effect of Tension

  27. Effect of Two Components and Asymmetry in Leaves SMALL HEADS, LARGE TAILS FAVORED HERE IN PROXIMAL LEAF

  28. Effect of Two Components and Asymmetry in Leaves Average concentration of hex-former is 0.35 0.35 in cis F/kbT 0.40 in cis 0.43 in cis f=0.4 (DOPC) and f=0.294 (DOPE)

  29. Effect of Two Components and Asymmetry in Leaves Average concentration of hex-former is 0.35 0.35 in cis F/kbT 0.40 in cis Note that stalk becomes metastable. Its formation is now largest barrier 0.43 in cis

  30. Effect of curvatureFusion of Bilayer and Vesicle: 1 bilayer =4.3 Rg 60:40 mixture J Y Lee & M.S. BJ 2008

  31. What should we expect the effect of curvature to be?

  32. As vesicle radius decreases, effective tension increases, which decreases barrier

  33. Fusion of two identical vesicles 60:40 mixture

  34. Control Fusion by Controlling the Interbilayer Spacing H = 2.2 R_g, zero tension, 60:40 mixture

  35. H = 2.2, 2.7 R_g, zero tension

  36. H = 2.2, 2.7, 3.2 R_g, zero tension

  37. H = 2.2, 2.7, 3.2, 3.7 R_g, zero tension

  38. H = 2.2, 2.7, 3.2, 3.7, 4.0 R_g, zero tension

  39. Conclusions • Two barriers to fusion

  40. Conclusions • Two barriers to fusion • Barrier to stalk formation linear in distance ->easy to prevent fusion

  41. Conclusions • Two barriers to fusion • Barrier to stalk formation linear in distance ->easy to prevent fusion • Second barrier reduced by composition and curvature

  42. Conclusions • Two barriers to fusion • Barrier to stalk formation linear in distance ->easy to prevent fusion • Second barrier reduced by composition and curvature • Consequently, when brought close, stalk barrier is small, ~13kT, and fusion is quick • Fusion on demand!

  43. Acknowledgements Marcus Mueller Kirill Katsov Jae-Youn Lee NSF Grant DMR 0503752

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