NIS metastable intermediates provide insights into conformational transition between principal thermodynamic states

The Sodium/Iodide Symporter (NIS), a thirteen-helix transmembrane protein found in the thyroid and other tissues, transports iodide, a required constituent of thyroid hormones T3 and T4. Despite extensive experimental information and clinical data, structural details of the intermediate microstates comprising the conformational transition of NIS between its inwardly and outwardly open states remain unresolved. We present data from a combination of enhanced sampling and transition path molecular dynamics (MD) simulations that elucidate the nature of the principal intermediate states comprising the transition between the inwardly and outwardly open metastable states of fully bound and unbound NIS under an enforced ionic gradient. Our findings suggest that in both the absence and presence of bound physiological ions, NIS principally occupies a proximally inward to inwardly open state, whereas when fully bound, it also occupies a rare but thermodynamically favorable inward occluded state. The results of this work provide novel insight into the populations of NIS intermediates and the free energy landscape comprising the conformational transition, adding to a mechanistic understanding of NIS ion transport. Moreover, the knowledge gained from this approach can serve as a basis for studies of NIS mutants to target therapeutic interventions. O_FIG O_LINKSMALLFIG WIDTH=192 HEIGHT=200 SRC="FIGDIR/small/512170v1_ufig1.gif" ALT="Figure 1"> View larger version (80K): org.highwire.dtl.DTLVardef@e826e0org.highwire.dtl.DTLVardef@1504d00org.highwire.dtl.DTLVardef@ef7104org.highwire.dtl.DTLVardef@1e4c95f_HPS_FORMAT_FIGEXP M_FIG For Table of Contents Only C_FIG