Molecular dynamics investigation of gluazo, a photo-switchable ligand for the glutamate receptor GluK2

Photochromic ligands (PCLs), defined as photoswitchable molecules that are able to endow native receptors with a sensitivity towards light, have become a promising photopharmacological tool for various applications in biology. In general, PCLs consist of a ligand of the target receptor covalently linked to an azobenzene, which can be reversibly switched between two configurations upon light illumination. Gluazo, as a PCL that targets excitatory amino acid receptors, in its dark-adapted trans iso-form was characterized to be a partial agonist of the kainate glutamate receptor GluK2. Application of UV light leads to the formation of the cis form, with remarkedly reduced affinity towards GluK2. The mechanism of the change of ligand affinity induced by the photoisomerization was unresolved. The presented computational study explains how the isomerization of such a PCL affects the structural changes in the target receptor that lead to its activation.

光致变色配体（Photochromic ligands, PCLs）是一类可光开关分子，能够赋予天然受体对光的敏感性，现已成为生物学领域各类应用中极具潜力的光药理学工具。通常来说，PCLs由与偶氮苯共价结合的靶受体配体组成，该偶氮苯可在光照下于两种构型之间可逆切换。靶向兴奋性氨基酸受体的PCL谷氮唑（Gluazo），其暗适应状态下的反式异构体被证实为红藻氨酸型谷氨酸受体GluK2的部分激动剂。紫外光照射可使其转化为顺式异构体，此时对GluK2的亲和力显著下降。此前，光异构化诱导配体亲和力改变的机制尚未阐明。本项计算研究阐明了此类PCL的异构化如何影响靶受体的结构变化，进而介导受体激活。