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. ![Figure][1] For Table of Contents Only ### Competing Interest Statement The authors have declared no competing interest. * NIS : Sodium/Iodide Symporter MD : molecular dynamics SLCA5 : solute carrier family 5 T3 : triiodothyronine T4 : tetraiodothyronine SCN− : thiocyanate ClO3− : chlorate ReO4− : perrhenate ClO4− : perchlorate vSGLT : Vibrio parahaemolyticus Na+/galactose transporter SiaT : Proteus mirabilis Na+- coupled sialic acid symporter ITD : iodide transport defect LeuT : Aquifex aeolicus Na+-dependent leucine transporter POPC : 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine DLPC : 1,2-dilauroyl-sn-glycero-3-phosphocholine SVM : Support Vector Machine [1]: pending:yes