Substrate Binding and Conformational Change of the Bile Acid Transporter ASBT$_{\mathrm{NM}}$

The apical sodium-dependent bile acid transporter (ASBT) allows reabsorption of bile acids from the intestine by coupling bile acid movement to the sodium gradient. Such transporters are attractive targets for drug delivery and in the treatment for hypercholesterolaemia. Several structures of bacterial homologues in both inward and outward facing conformations have been obtained experimentally, including a substrate-bound inward facing structure of the homologue from Neisseria meningitidis (ASBT$_{\mathrm{NM}})$. However, many details surrounding the binding of substrates and the conformational transition remain unclear. We have used computational methods to explore these details at an atomistic scale using the homologue ASBT$_{\mathrm{NM}}$ and the bile acid taurocholate. Models of \textit{apo }and substrate-bound ASBT$_{\mathrm{NM\thinspace }}$in the outward-facing conformation were generated. Biased molecular dynamics simulations were used to explore potential conformational changes and taurocholate movement, while alternate binding sites and the residues important for sodium and taurocholate binding were investigated with unbiased simulations. These results further our understanding of the important molecular details of ASBT function.