Calcium Permeation across the AMPA Receptor Channel: a Combined MD and QM/MM Study

The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR) are neurotransmitter-activated cation channels ubiquitously expressed across vertebrate brains. The regulation of calcium flux through the channel pore by RNA-editing is linked to synaptic plasticity while excessive calcium influx poses a risk of neurodegeneration. Unfortunately, the molecular mechanisms underlying this key process are still unknown. Here, Molecular Dynamics (MD) simulations employing recently reported multi-site force field parameters for Ca2+ revealed abundant calcium permeation through the unedited form of the GluA2 channel that is in good agreement with experimental data. An additional binding site of Ca2+ enabled by the side-chain of glutamine at the Q/R editing site provides an explanation of the calcium permeability difference in different RNA-edited forms of GluA2. For one of the identified metal binding sites, multi-scale Quantum Mechanics/ Molecular Mechanics (QM/MM) simulations reproduced the Ca2+ hydration statistics emerging from MD simulations. Critically, they also revealed small but reproducible charge transfer between the metal ion and its first solvation shell. The resulting polarization of the bound water likely impacts the hydrogen bond network of hydrated calcium ions in the channel. We suggest that the new Ca2+ parametrization paves the way to provide insight also into other proteins where calcium plays a pivotal role and that even more accurate predictions may be obtained by including electronic polarization in the simulations.