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Atomic Resolution Description of the Transport Cycle in Neurotransmitter

Emad Tajkhorshid, University of Illinois at Urbana-Champaign

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John Stone, David Hardy, Emad Tajkhorshid, Po-Chao Wen, Jing Li, Paween Mahinthichaichan, Christopher Mayne, Michael Robson, Yuhang Wang, Rezvan Shahoei, Rafael Bernardi, Mrinal Shekhar, Sundarapandian Thangapandian, Marcelo Dos Reis Melo, Ronak Buch, Noah Trebesch, Muyun Lihan, Melanie Muller, Tao Jiang, Zhiyu Zhao, Eric Shinn, Ahmad Raeisi Najafi, Kin Lam, Andres Arango, Shashank Pant, Nandan Haloi, Chang Sun, Jaemin Choi, - Senthil Kumar Karthik

The overarching goal of the project is to characterize large-scale structural transitions in dopamine transporter (DAT) between its major functional states. DAT, a major neurotransmitter transporter, plays a fundamental role in uptake of neurotransmitter molecules, and is therefore of high relevance to human physiology and disease. The description of large-scale protein structural changes at high (atomic) resolutions requires sampling high-dimensional free energy landscapes that are inaccessible to conventional simulation techniques such as regular molecular dynamics (MD) simulations. We have developed and tested a novel computational approach using nonequilibrium methods employing system-specific collective variables and a combination of several state-of-the-art sampling techniques that, while numerically expensive, has proven to be one of the most effective techniques to describe such large-scale structural transitions. The approach is based on loosely coupled, multiple-copy MD simulations of large macromolecular systems, which require massive computing resources; hence this project is only possible on platforms such as Blue Waters.