Model Construction from Multi-scale Multi-modal Data on Trans-synaptic Structures: Assembling Molecular and Cellular Data on Neurexin-Neuroligin Complexes


Biological Significances:  

The immediate biomedical impact pertains to developmental disorders, but implications are much broader, including neurodegenerative disease and aging.  

Project Summary:

This project brings together efforts of multiple laboratories, each obtaining data with different methods related to synapse formation and stabilization. The work bridges molecular structure of key molecules with high resolution/mesoscale 3D microscopy using new genetic probes for correlated light and electron microscopy (EM). The main outcome of the work is the assembly of a molecular-to-cellular scale model of two of the key bridging proteins at synapses, neurexin and neuroligin, aligning structural details from crystallographic studies with emerging results from in situ EM showing patterning of these molecules bridging the synaptic cleft. We bring together diverse expertise in developing new molecular probes for structural labeling of complex biological environments using electron and correlated light microscopes (performed at NCMIR), tomographic reconstruction technologies, simulation and computer-aided drug-discovery workflow development, emerging cyberinfrastructure technologies, and domain-specific interface development to enable the discovery of small-molecule compounds. We advance NBCR technologies through the development of workflows related to relaxed complex scheme methodologies (and tools that enable exploration of enhanced sampling methods (accelerated molecular dynamics) in drug discovery. This project will also drive the development of massively parallelized molecular dynamics simulation technologies being developed at the National Center for Macromolecular Modeling and Bioinformatics.


Key Outcomes:

  • Loh KH, Stawski PS, Draycott AS, Udeshi ND, Lehrman EK, Wilton DK, Svinkina T, Deerinck TJ, Ellisman MH, Stevens B, Carr SA, Ting AY. Proteomic Analysis of Unbounded Cellular Compartments: Synaptic Clefts. Cell. 2016;166(5):1295-307 e21. doi: 10.1016/j.cell.2016.07.041.
  • Miao Y, Feher VA, McCammon JA. Gaussian Accelerated Molecular Dynamics: Unconstrained Enhanced Sampling and Free Energy Calculation. J Chem Theory Comput. 2015;11(8):3584-95. doi: 10.1021/acs.jctc.5b00436. 
  • Purawat P, Ieong P, Malmstrom RD, Chan G, Walker RC, Yeung AK, Altintas I, Amaro RE. A Kepler Workflow Tool for Reproducible Molecular Dynamics. Biophsyical J. (Submitted).