Molecular Dynamics Simulations of the Proteins Regulating Synaptic Vesicle Fusion

Neuronal transmitters are packaged in synaptic vesicles (SVs) and released by the fusion of SVs with the presynaptic membrane (PM). An inflow of Ca(2+) into the nerve terminal triggers fusion, and the SV-associated protein Synaptotagmin 1 (Syt1) serves as a Ca(2+) sensor. In preparation for fusion, SVs become attached to the PM by the SNARE protein complex, a coiled-coil bundle that exerts the force overcoming SV-PM repulsion. A cytosolic protein Complexin (Cpx) attaches to the SNARE complex and differentially regulates the evoked and spontaneous release components. It is still debated how the dynamic interactions of Syt1, SNARE proteins and Cpx lead to fusion. This problem is confounded by heterogeneity in the conformational states of the prefusion protein–lipid complex and by the lack of tools to experimentally monitor the rapid conformational transitions of the complex, which occur at a sub-millisecond scale. However, these complications can be overcome employing molecular dynamics (MDs), a computational approach that enables simulating interactions and conformational transitions of proteins and lipids. This review discusses the use of molecular dynamics for the investigation of the pre-fusion protein–lipid complex. We discuss the dynamics of the SNARE complex between lipid bilayers, as well as the interactions of Syt1 with lipids and SNARE proteins, and Cpx regulating the assembly of the SNARE complex.