Computational Studies of the Molecular Mechanisms Responsible for Ca2+ Permeation and Mg2+ Block of NMDA Receptors

Abstract

Glutamate receptors are membrane proteins activated by the neurotransmitter glutamate that mediate fast synaptic excitation in the mammalian brain. NMDA receptors constitute a glutamate receptor subfamily specifically activated by N-methyl-d-aspartate. Due to their high Ca2+ permeability and voltage-dependent channel block by Mg2+, NMDA receptors play a central role in development through stabilization of synaptic connections, as well as in learning and memory by mediating many forms of synaptic plasticity. The mechanisms by which the ion channel of NMDA receptors selects Ca2+ for permeation over all other physiological ions, while binding Mg2+ and restricting its permeation, are not well understood. We hypothesize that the slightly different radii and electronic properties of Mg2+ and Ca2+ ions result in drastically different free energy barriers for transition of the ions from a binding site in the selectivity filter toward the intracellular solution. We are applying quantitative theoretical “bottom up” approaches to this complex system by combining methods of computational chemistry, molecular mechanics (MM), and bioinformatics. The structure of the NMDA receptor channel is constructed and refined using experimental information, homology modeling and extensive molecular dynamics simulations. We are performing quantum chemical calculations to determine the energy of the transition state of model ligand exchange reactions that mimic divalent ion transition from the selectivity filter of NMDA receptors to water. Quantum calculations are used to parameterize a polarizable molecular mechanics force field for these divalent ion interactions with organic ligands with the further goal to perform MM simulations. Umbrella sampling and thermodynamic integration simulations are used to compute free energies of transfer of divalent ions between water and a model of the NMDA ion selectivity filter as well as free energy barriers for these transitions.