Emerging Concepts in Ion Channel Biophysics

Emerging Concepts in Ion Channel Biophysics

Poster Abstracts

10-POS

Board 10

Investigating Dynamics of the NMDA Receptor Using Molecular Dynamics Simulations

Nils Berglund

, Birgit Schiøtt.

Aarhus University, Aarhus, Jutland, Denmark.

The NMDA receptor (NMDAR) is part of the ionotropic glutamate receptor family. Present in

the majority of excitatory synapses, these membrane spanning proteins form heterotetramers and

are activated through binding of both glycine and glutamate, to binding sites present in the

membrane adjacent ligand-binding domain. Neurotransmitter binding leads to conformational

changes that open the channel region of the protein allowing an influx of Ca

in the postsynaptic

neuron, leading to depolarization and signal transduction. NMDAR is essential for brain function

and brain development, crucially in the areas of learning and memory formation. The

dysregulation of this receptor has been implicated in a large number of neurological conditions

and it is therefore a promising target in the treatment of Alzheimer's disease, epilepsy,

schizophrenia, depression as well as several other conditions.

The objective of our work was to improve the understanding of the dynamic nature of NMDAR

and the effect neurotransmitter binding had on protein dynamics. Thanks to recently released,

high resolution structures from X-ray crystalography and cryo-EM studies, this protein can now

be studied computationally at the atomistic level. Furthermore these structures have

demonstrated that NMDAR has a highly dynamic nature with a significant number of well

defined and distinct conformational states. Using molecular dynamics simulations we

investigated the effects of neurotransmitter binding on full heterotetrameric NMDAR structures

bound to a POPC membrane. Initial results show early stages of conformational transitions as a

result of ligand binding.