Conformational spread and dynamics in allostery of NMDA receptors

Significance NMDA receptors are the main excitatory receptors in the mammalian central nervous system. They require the binding of both glutamate and glycine for the activation of the protein. However, the binding of one agonist lowers the affinity of the second. The mechanism and physiological significance of this negative cooperativity between the two agonists is currently unknown. Using single molecule FRET and MD simulations we show that binding of one agonist destabilizes the second agonist-binding domain, making it less favorable to bind the second agonist, thus leading to lower affinity. Additionally, there is minimal effect on the transmembrane segments in the presence of a single agonist thus ensuring that the protein is activated only when bound to both agonists.