CONFORMATIONAL CHARACTERIZATION IN THE NIS SIMPORTER: ORDER PARAMETER FOR ALPHA HELICE LIPIDS

The importance of studying the Na⁺/I⁻ symporter (NIS) lies in its fundamental role in human physiology, as it mediates the active transport of iodide ions into the thyroid gland. This process is the first step in the biosynthesis of thyroid hormones, which are of vital importance for the regulation of cellular metabolism at all stages of life, as well as for embryonic and nervous system development. Its ability to transport diverse substrates and isotopes has positioned it as a key tool in advanced medical imaging techniques, as well as in the treatment of thyroid cancer. Currently, kinetic and structural experimental studies are available, the latter primarily obtained through X-ray diffraction crystallography and cryogenic electron microscopy (cryo-EM). Over the last two decades, with the aid of these studies, the transport mechanism of  𝐼− through NIS has been proposed, which still possesses steps that are not completely understood in a comprehensive manner from a biochemical, structural, and biothermodynamic perspective. For these reasons, molecular dynamics (MD) simulations are highly beneficial, as they have been shown to provide complementary information for this type of problem. To this end, MD trajectories have been generated in the NPT ensemble on the order of microseconds. The structural configurations of this simulation include a high-resolution NIS structure embedded in a membrane with highly physiological characteristics, along with concentrations of chloride, sodium, potassium, and iodide ions, as well as rhenium. This simulation also includes electrical potentials in order to model the entire system in a highly realistic environment. From this, it has been possible to verify some of the intermediate conformations initially proposed for the transport mechanism in NIS. Furthermore, the simulation suggests the presence of, apart from independent conformational changes, other types of movements identified as concerted conformational changes. For this reason, in this study we aim to verify (work in progress) this type of concerted molecular movements using a statistical mechanical order parameter that will eventually allow us to find these correlations.