Computer Simulation Studies of a Kainate (GluK1) Receptor with Two Glutamate Analogues

Abstract

Unprecedented advancements have been achieved to understand the underlying mechanisms that sustain life. The modulation of these mechanisms, especially in disease conditions, could lead to the development of new medical applications. However, to attain this goal, we need to characterize life processes at the molecular level. Unfortunately, the majority of current experimental techniques used in life sciences lack this resolution. In this work, we have used molecular dynamics, a computational “microscopy”, to gain insight into the mechanism of interaction, at the atomic level, between two bicyclic glutamate analogues with the ligand–binding domain (LBD) of a kainate receptor 1 (GluK1). This protein receptor plays a crucial role in the development of various central nervous system (CNS) disorders such as Alzheimer’s disease, epilepsy and depression. Here we report the outcome of Molecular Dynamics (MD) simulations to calculate the affinity of binding of two ligands, the glutamate analogues LM-12b and CIP-AS, toward the LBD of GluK1 (GluK1–LBD) and to unravel, at the atomic level, the structural dynamics of such interactions. Our computational approach not only was capable of ranking correctly the binding affinity of analyzed ligands toward the protein receptor, but also to reveal, at atomic resolution, the dynamic nature of such ligand–LBD interaction. Our studies showed that the methyl group of LM-12b is crucial to stabilize structurally the LBD pocket. In contrast, the LBD–CIP-AS complex lacked this interaction, which may explain its weaker affinity. Revealing the structural and dynamics bases that underlie the mechanism of ligand–kainate receptor interaction may ultimately drive the identification of new modulators aimed at the treatment of CNS disorders.