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NMDA Receptor Transmembrane Domain: Structure and Divalent Ion Se.pdf (12.97 MB)

NMDA Receptor Transmembrane Domain: Structure and Divalent Ion Selectivity

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posted on 2014-05-01, 00:00 authored by Lea Veras

During a synaptic signal, NMDA receptors are the only ionotropic glutamate receptor subfamily that besides glutamate require glycine and membrane depolarization to allow ion permeation. The depolarization is necessary to release Mg2+ of the channel of NMDA receptors. Of the ions that permeate these ion channels, Ca2+ is of importance because it is essential for learning and memory. Furthermore, NMDA receptor dysfunction has been associated with several nervous system disorders, and thus understanding NMDA receptor functions and dysfunctions are relevant for rational drug design. The mechanisms by which NMDA receptors select Ca2+ for permeation over all other physiological ions, while binding Mg2+ and restricting other ions’ permeation, are not well understood. We hypothesize that the slightly different atomic properties of Mg2+ and Ca2+ result in different mechanisms for how each divalent ion moves across the channel. To create a more complete picture of the permeation mechanism and prove our hypothesis, we performed a multi-level computational chemistry approach. Our research methods consisted of three main steps. The first step was to perform quantum chemical and molecular dynamic calculations to quantitatively predict ion interactions with solvents that mimic the heterogeneous environment of the protein. The second step consisted of modeling, refining, and equilibrating a homology model of the NMDA receptor transmembrane domain. The final step consisted of using the equilibrated transmembrane domain NMDA receptor model to study the actual ionic environment in the protein and simulate the energy involved in the permeation process. For the first step, we found that the solvents mimic the behavior of the residues in the core of our NMDA receptor model because in both set of systems Ca2+ is more permissive than Mg2+ to exchange ligands. As the conclusions in second and third steps, we also observed that the aspargines in the NMDAR model provide the ideal cage environment, that functions like branches and capture the each divalent ion. Hence, an equilibrated TMD NMDAR model was built, the presence of each divalent ion in the protein was simulated, and the permeation mechanism was better understood.

History

Date

2014-05-01

Degree Type

  • Dissertation

Department

  • Chemistry

Degree Name

  • Doctor of Philosophy (PhD)

Advisor(s)

Maria Kurnikova

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