Atomic Resolution Description of the Transport Cycle in Neurotransmitter
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.