Fortoul Nicole, Singh Pankaj, Hui Chung-Yuen, Bykhovskaia Maria, Jagota Anand
Department of Chemical and Biomolecular Engineering, Lehigh University, Bethlehem, Pennsylvania.
Department of Mechanical & Aerospace Engineering, Cornell University, Ithaca, New York.
Biophys J. 2015 May 5;108(9):2258-69. doi: 10.1016/j.bpj.2015.03.053.
Synaptic transmission requires that vesicles filled with neurotransmitter molecules be docked to the plasma membrane by the SNARE protein complex. The SNARE complex applies attractive forces to overcome the long-range repulsion between the vesicle and membrane. To understand how the balance between the attractive and repulsive forces defines the equilibrium docked state we have developed a model that combines the mechanics of vesicle/membrane deformation with an apparently new coarse-grained model of the SNARE complex. The coarse-grained model of the SNARE complex is calibrated by comparison with all-atom molecular dynamics simulations as well as by force measurements in laser tweezer experiments. The model for vesicle/membrane interactions includes the forces produced by membrane deformation and hydration or electrostatic repulsion. Combining these two parts, the coarse-grained model of the SNARE complex with membrane mechanics, we study how the equilibrium docked state varies with the number of SNARE complexes. We find that a single SNARE complex is able to bring a typical synaptic vesicle to within a distance of ∼ 3 nm from the membrane. Further addition of SNARE complexes shortens this distance, but an overdocked state of >4-6 SNAREs actually increases the equilibrium distance.
突触传递要求充满神经递质分子的囊泡通过SNARE蛋白复合体停靠在质膜上。SNARE复合体施加吸引力以克服囊泡与膜之间的长程排斥力。为了理解吸引力和排斥力之间的平衡如何定义平衡停靠状态，我们开发了一个模型，该模型将囊泡/膜变形的力学与一个明显新颖的SNARE复合体粗粒度模型相结合。通过与全原子分子动力学模拟以及激光镊子实验中的力测量结果进行比较，对SNARE复合体的粗粒度模型进行了校准。囊泡/膜相互作用模型包括膜变形以及水化或静电排斥产生的力。将SNARE复合体的粗粒度模型与膜力学这两部分结合起来，我们研究了平衡停靠状态如何随SNARE复合体的数量而变化。我们发现单个SNARE复合体能够使典型的突触囊泡与膜的距离缩短至约3纳米以内。进一步添加SNARE复合体会缩短这个距离，但超过4 - 6个SNARE的过度停靠状态实际上会增加平衡距离。
