Computational techniques to illuminate secrets of the monoamine transporters.

摘要

The solute carrier family regulates the flow of various substances such as drugs, amino acids, sugars and inorganic ions across the cell membrane. In particular, the monoamine transporters (MATs) are responsible for the regulation of synaptic neurotransmitter levels. Their structures and conformational rearrangements associated with transport remain unsolved. We employed novel computational techniques to identify the binding pocket of cocaine in the dopamine transporter (DAT) and two intracellular pathways for substrate egress in LeuT and DAT. We review possible coarse grained molecular dynamics techniques to extend the temporal scale accessible in simulations of the MATs. Finally, we present the first computational study of DAT in the presence of an explicit electrochemical gradient. In these simulations, we identify a water wire in DAT that may suggest that DAT does not follow an alternating access mechanism.