Context and objective

The Biomechanics team at the MSME laboratory (Université Paris-Est Créteil) is developing a research partnership with the Paris Cardiovascular Research Center to create a mechanical model (Figure 1) of a high-throughput assay for testing the effects of drugs on cardiac tissue (Figure 2).

M. Caruel, the project leader in the Biomechanics group, is seeking a highly motivated student to contribute to the development, calibration, and validation of this model in close collaboration with members of PARCC.

The model is based on an existing formulation (Caruel et al. 2014), which will need to be adapted to the experimental setup and implemented within an existing simulation framework.
Available experimental data will be used for model calibration and validation.
The student may also participate in the experimental work.

The internship will be based at MSME in Créteil, with regular meetings at PARCC in Paris.

Profile

We are seeking a person with a strong academic background in solid mechanics, ideally with familiarity in large deformation theory. In addition, the recruit should have proven programming skills to understand the existing simulation framework and develop new libraries.

Contact

Matthieu Caruel: matthieu.caruel@u-pec.fr

Abstract

During neurotransmission, neurotransmitters are released less than a millisecond after the arrival of the action potential. To achieve this ultra-fast event, the synaptic vesicle must be pre-docked to the plasma membrane. In this primed state, SNAREpins, the protein-coiled coils whose assembly provides the energy to trigger fusion, are partly zippered and clamped like a hairpin and held open and ready to snap close when the clamp is released. Recently, it was suggested that three types of regulatory factors, synaptophysin, synaptotagmins, and complexins act cooperatively to organize two concentric rings, a central and a peripheral ring, containing up to six SNAREpins each. We used a mechanical model of the SNAREpins with two separate states, half-zippered and fully zippered, and determined the energy landscape according to the number of SNAREpins in each ring. We also performed simulations to estimate the fusion time in each case. The presence of the peripheral SNAREpins generally smoothens the energy landscape and accelerates the fusion time. With the predicted physiological numbers of six central and six peripheral SNAREpins, the fusion time is accelerated at least 100 times by the presence of the peripheral SNAREpins, and fusion occurs in less than 10 μs, which is well within the physiological requirements.

Reference

@Article{biom14050600,
AUTHOR = {Caruel, Matthieu and Pincet, Frédéric},
TITLE = {Dual-Ring SNAREpin Machinery Tuning for Fast Synaptic Vesicle Fusion},
JOURNAL = {Biomolecules},
VOLUME = {14},
YEAR = {2024},
NUMBER = {5},
ARTICLE-NUMBER = {600},
URL = {https://www.mdpi.com/2218-273X/14/5/600},
DOI = {10.3390/biom14050600}
}

Abstract

During neurotransmission, neurotransmitters are released less than a millisecond after the arrival of the action potential. To achieve this ultra-fast event, the synaptic vesicle must be pre-docked to the plasma membrane. In this primed state, SNAREpins, the protein-coiled coils whose assembly provides the energy to trigger fusion, are partly zippered and clamped like a hairpin and held open and ready to snap close when the clamp is released. Recently, it was suggested that three types of regulatory factors, synaptophysin, synaptotagmins, and complexins act cooperatively to organize two concentric rings, a central and a peripheral ring, containing up to six SNAREpins each. We used a mechanical model of the SNAREpins with two separate states, half-zippered and fully zippered, and determined the energy landscape according to the number of SNAREpins in each ring. We also performed simulations to estimate the fusion time in each case. The presence of the peripheral SNAREpins generally smoothens the energy landscape and accelerates the fusion time. With the predicted physiological numbers of six central and six peripheral SNAREpins, the fusion time is accelerated at least 100 times by the presence of the peripheral SNAREpins, and fusion occurs in less than 10 μs, which is well within the physiological requirements.

Reference

@Article{biom14050600,
AUTHOR = {Caruel, Matthieu and Pincet, Frédéric},
TITLE = {Dual-Ring SNAREpin Machinery Tuning for Fast Synaptic Vesicle Fusion},
JOURNAL = {Biomolecules},
VOLUME = {14},
YEAR = {2024},
NUMBER = {5},
ARTICLE-NUMBER = {600},
URL = {https://www.mdpi.com/2218-273X/14/5/600},
DOI = {10.3390/biom14050600}
}