# Modeling SNARE-Mediated Membrane Fusion

> **NIH NIH R01** · COLUMBIA UNIV NEW YORK MORNINGSIDE · 2020 · $316,198

## Abstract

PROJECT SUMMARY
Membrane fusion, the merging of two membranes into a single continuous phospholipid bilayer, is central to
intracellular trafficking, secretion, fertilization and other processes vital to living organisms. To fuse membranes,
cells use a machinery whose core consists of the SNARE proteins. During exocytosis, neurotransmitters or
hormones are released by neurons or endocrine cells, respectively, when synaptic vesicles or secretory granules
fuse with the plasma membrane, driven by complexation of vesicular v-SNAREs with plasma membrane t-
SNAREs that assemble into SNAREpin complexes. SNAREpin assembly pulls the membranes together and
provokes their fusion. The result is a fusion pore which allows vesicle contents to be released through the plasma
membrane. Exocytotic fusion pores, widely studied electrophysiologically, often flicker open and closed
repeatedly before resealing (“kiss and run” fusion) or dilating (“full fusion”).
The detailed mechanism of SNARE-mediated fusion is unknown. It is thought that once a fusion pore is created,
SNAREs participate in regulating pore dynamics and openness post-fusion, thereby regulating the amount and
rate of contents released. However, the mechanisms underlying this regulation are not known.
A major obstacle to answering these questions has been the lack of quantitative modeling approaches that can
access physiologically relevant fusion timescales (msec-sec). Atomistic and current coarse-grained molecular
dynamics (MD) simulation approaches yield vital information, but due to computational limitations cannot
describe long time collective fusion phenomena. We will develop two coarse-grained methods to access the
necessary timescales. One is a coarse-grained continuum approach, with bilayers represented as continuous
fluctuating deformable surfaces; the other a more detailed MD simulation adapting an existent simulation with
highly coarse-grained explicit phospholipids. A multiscale strategy is proposed: both methods coarse-grain the
SNAREs, but dimensions, surface charge, zippering energy landscape and other features will be described by
realistic parameters from experiment or less coarse grained simulations. These methods will simulate many
SNAREpins at the pre-fusion site to assess if they cooperatively fuse membranes, and to map the network of
pathways to fusion that may involve hemifused or extended contact intermediate states. We will then simulate
the dynamical fusion pore itself and study for the first time how the forces from assembled SNAREpins affect
the flickering dynamics and dilation of the pore. Once working simulations of multiple SNAREpins operating
between dynamic membranes are in place, we will progressively “reconstitute” the fusion machinery with
successive layers of complexity, adding the SNARE regulating proteins complexin and synaptotagmin to test
candidate mechanisms whereby these components clamp or activate SNARE-mediated fusion. These enlarged
models will be used to b...

## Key facts

- **NIH application ID:** 9986817
- **Project number:** 5R01GM117046-04
- **Recipient organization:** COLUMBIA UNIV NEW YORK MORNINGSIDE
- **Principal Investigator:** Ben O'Shaughnessy
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $316,198
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9986817

## Citation

> US National Institutes of Health, RePORTER application 9986817, Modeling SNARE-Mediated Membrane Fusion (5R01GM117046-04). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/9986817. Licensed CC0.

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