Towards elucidating mechanisms of synaptic vesicle fusion: A computational study

Objective: Neurotransmission, a process by which neurotransmitters are released from synaptic vesicles to the synaptic cleft, is essential for the neuron communication. Each neurotransmitter can influence neurons in the brain and affect the behavior during the neurotransmission. The misfortune in the neurotransmitter release can cause several neurological complications such as depression, Parkinson’s disease, Alzheimer’s disease and autism. As a critical step in the neurotransmitter release process, synaptic vesicle fusion requires vesicle membrane and plasma membrane fusion, which in turn, is facilitated by the protein machinery including SNARE complex. However, how this protein machinery helps with synaptic vesicle fusion remains unclear because the highly dynamic feature of this machinery greatly challenges currently available experimental methods. The goal of this study is to build a computational model to simulate the synaptic vesicle fusion process. Methods: Chemistry at Harvard Molecular Mechanics (CHARMM) and Visual molecular dynamics (VMD) were used to generate SNARE/membrane complexes. The MD simulations were performed using Nanoscale Molecular Dynamics simulator on Texas Advanced Computing Center. CHARMM27 general force field was implemented to solve the equations of motion in 3D PBC. The Particle Mesh Ewald algorithm was used to calculate long-range Coulomb interactions. Results: We built a novel all-atom computational model including SNARE complex, vesicle membrane and plasma membrane. The bicelle model of these membranes was stabilized by DHPC present in 20 nm edge of each membrane. SNARE molecules were preferentially arranged in trigonal planar and pentagonal planar conformations between vesicle membrane and plasma membrane separated at 20 angstroms apart from one another. In each of the planar conformations, SNARE molecules are arranged is such a way that C-terminals are towards the center of membranes and N-terminals are towards the edge of membranes. The transmembrane region (TMR) helices of syntaxin-1 and synaptobrevin were stabilized deep inside the plasma and vesicle membrane, respectively. Conclusions: We successfully built a novel computational model at atomic level to simulate synaptic vesicle fusion process. The conformational dynamics of SNARE/membrane complex were investigated at the molecular level. Our efforts provided a novel tool and revealed new insights towards a clear understanding of the mechanism of neurotransmission.