Mostly Biomathematics Lunchtime Seminar
Ultra coarse grained modeling of neurotransmitter release
Speaker: Ben O’Shaughnessy, Department of Chemical Engineering, Columbia University
Location: Warren Weaver Hall 1314
Date: Tuesday, April 23, 2019, 12:30 p.m.
Synopsis:
Cognition, sensation, and coordinated motor activity rely on tightly controlled release of neurotransmitters (NTs) at neuronal synapses. NTs are released from synaptic vesicles docked at the plasma membrane, accomplished by a synaptic machinery that senses Ca2+ when a pre-synaptic action potential arrives, responds by fusing the vesicular and neuronal plasma membranes, and releases NTs through a fusion pore. How the NT release machinery works remains poorly understood. However, key molecular components are now identified and characterized, and how the pieces fit together is beginning to emerge from crystal structures. This information has opened the door to realistic, molecularly explicit mathematical modeling of the machinery.
I will describe our efforts to represent this machinery computationally. The key to our approach is a molecularly explicit representation sufficiently coarse-grained to access collective behavior on the long timescales of physiological fusion. This is far beyond the scope of all-atom or mildly coarse-grained approaches. Our simulations describe a 3-stage NT release process: first, Synaptotagmin-mediated Ca-triggered unclamping of the core SNARE machinery; second, self-assembly of SNARE complexes into an organized ring at the fusion site; third, SNARE-mediated fusion of the membranes and initiation of NT release. The second and third stages are spontaneous, driven by entropic forces among fully zippered SNARE complexes. We calculate fusion rates versus [Ca] and the number of SNAREs, and we compare with electrophysiological and other experimental measurements.