Fundamental mechanisms in cell function and communication (e.g., in the brain) are understood only phenotypically based on inferences from experiments that do not reach down to molecular scale. This is clearly not an ideal position from which to address disease, attempt to mitigate the effects of toxic environments, or employ the richness of biological templates to guide nanotechnology or the design of complex molecular machines. The discovery and quantifications of the underlying fundamental molecular processes that are needed to accomplish these important tasks is a grand challenge in current biomedicine and biophysics. In this project, Weinstein’s team will use computational simulation and analysis to take advantage of the precious structural and functional data provided by crystallography, nuclear magnetic resonance spectroscopy, ultra-resolution microscopy, and cryo–electron microscopy at the required atomic or near-atomic resolution in order to uncover and quantify the dynamic molecular mechanisms of complex molecular machines. By using advanced mechanistic analyses of trajectories from molecular dynamics dynamics simulations at unprecedented scales, the team will discover the molecular mechanisms of the functions and properties that are found in eukaryotic but not prokaryotic neurotransmitter transporters in the same (neurotransmitter:sodium symporters) class (e.g., the switch of activity from reuptake to efflux) in order to achieve a novel level of understanding of biological functions and to enable designs of synthetic analogs of such molecular machines with specifically engineered properties and functions.
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