The functional mechanisms of membrane proteins involved in cell signaling require dynamic coupling between the conformations of relatively discrete structural domains within the protein. Biochemical and biophysical studies have revealed such couplings over long molecular distances. We discuss quantitative representations of such biomolecular “action at a distance”, i.e., allostery, in structure-based models of function in a major membrane protein family: the neurotransmitter:Na+ symporters, NSS. Crystal structures of various NSS constructs (LeuT, dDAT, SERT) enabled our combinations of experimental and computational simulation studies resulting in detailed mechanistic insights. Incorporating novel quantitative methods in the computational approaches we described correlated dynamics of distal regions in the NSS, using allosteric models interrogated for quantitative inferences about allosteric mechanisms. Such physics-based analyses of extensive MD simulations reveal with increasing accuracy the molecular mechanisms of substrate and ion movements in the transporters, and the functional association of NSS family proteins with regulators and membrane components that are essential for function.

Allosteric functional mechanisms of molecular machines in the cell membrane

253rd National Meeting (2017)

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