Abstract
N-methyl-D-aspartate (NMDA) receptor activity produces calcium-rich excitatory currents that control the
physiology of central synapses. Ongoing excitatory transmission through NMDA receptors is essential for
moment by moment consciousness and cognition. In addition, permeating calcium drives long-term changes in
the strength of synapses to initiate learning and memory formation. Excessive NMDA receptor-mediated calcium
entry kills neurons and is a disease mechanism in stroke and age-related chronic pathologies such as
Alzheimer’s and Parkinson’s. Despite being sensitive to multiple small-molecule modulators, the potential of
NMDA receptors as therapeutic targets remains unrealized due to insufficient knowledge about the structural
changes that make their activation reaction. Moreover, recent advances in diagnosis with genetic sequencing
has identified a large number of unique variants in patients with neuropsychiatric disorders. Many of these
variants are causal to the disease, but the mechanism by which they affect the reaction mechanism, and
therefore function is unknown.
The overall objective of this research program is to describe the NMDA receptor activation, which consists of
stochastic transitions between closed, open, and desensitized states, with a level of detail that integrates atomic-
level structural information obtained from static receptor conformations with coarse-grained and atomistic
molecular dynamic simulations. These structural results will be tested with kinetic and thermodynamic
measurements of NMDA receptor current output.
At the completion of the proposed study, we will have identified atomic structures representative for each of the
three main functional states (closed, open, desensitized) and how these structures interconvert; will delineate
key atomic interactions that control these changes in structure; and will describe how the dynamic distribution of
receptors across this conformational landscape controls the patterns of depolarization and calcium influx
produced by NMDA receptors. Furthermore, we will then interrogate the resulting integrated mechanism to
examine how disease-related mutations and small-molecule modulators affect the conformational dynamics of
receptors and how they alter the NMDA receptor current.
The project will produce a congruent model that can be used to develop small-molecule modulators targeted to
specific receptor conformations that would reduce calcium flux independently of excitatory action, and will guide
therapeutic approaches for patients with dysfunctional NMDA receptor genetic variants.