Structural and dynamical characterization of presynaptic Active Zone

Prof. Dr. Cecilia Clementi

October 17, 2022

Our group works on the definition and implementation of strategies to study complex biophysical processes on long timescales. Despite the significant advances, our quantitative understanding of biological function at the molecular and cellular level is still in its relative infancy. Experimental and theoretical approaches to characterize macromolecular dynamics and function have evolved dramatically in the last few decades. However, experiment and computation have co-existed with limited feedback. On one hand, simulations can, in principle, resolve details not accessible to experiment, but are based on empirical models and, alone, cannot be quantitatively predictive. On the other hand, a wealth of indirect data on the structure and dynamics of macromolecular complexes is available from thermodynamic and kinetic measurements on parts of the systems of interest, but there is no way to systematically combine these data into a structural model.  We design multiscale models, adaptive sampling approaches, and data analysis tools that allow exploring large regions of a system's free energy landscape. We use data-driven methods for systematic coarse-graining of macromolecular systems, to bridge molecular and cellular scales. We work on a theoretical formulation to exploit the complementary information that can be obtained in simulation and experiment, to combine the approximate but high-resolution structural and dynamical information from computational models with the “exact” but lower resolution information available from experiments.

Project: The microscopic mechanisms that allow two neurons to communicate involve the release of neurotransmitters. Often, these neurotransmitters are encapsulated into vesicles, which facilitates their transport and release from the cytomatrix of the Pre-Synaptic Active Zone to the Post-Synaptic region. The cascade of events at the neuronal junction is regulated by several macromolecules.

The goal of our project is to predict the structure and dynamics of the proteins involved in the Active Zone, starting from the Bruchpilot protein (BRP), using theoretical and computational tools, in combination with experimental measurements. BRP is known to play a fundamental role in recruiting synaptic vesicles and transporting them to the membrane, in the brain of the fruit fly. We will build a multiscale computational model of BRP that is integrated with experimental data such as crosslinking and fluorescence data. From a methodological perspective, we will build a framework that can be used to integrate experimental data into computer simulations of complex macromolecular systems.

This project is in collaborations with the Genetics group of Prof. Dr. Stephan Sigrist in the FU Department of Biology and with Structural Biochemistry group of Prof. Dr. Markus Wahl.


For more information, visit the website of the Theoretical and Computational Biophysics Group

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