Grand Challenge: a single hydrogen bond controls ion channel function

22.03.2012

The Grand Challenge project led by Adjunct Professor Olli Pentikäinen (University of Jyväskylä) studied the functioning of glutamate receptors through molecular dynamics simulations. Glutamate receptors are synaptic proteins that play a central role in facilitating signal transmission from neuron to neuron. Ionotropic glutamate receptors have been found to be relevant to such as memory and learning. The functioning of these receptors is also associated with the development of a number of neurological diseases, such as epilepsy, migraine and Parkinson’s disease. A better understanding of the structure and functioning of the receptors thus has a high scientific impact in medicine.

The basic constituents of ionotropic glutamate receptors, or protein complex monomers, consist of extracellular N-terminal and  ligand-binding domains, a transmembrane channel and an intracellular domain.  As the activating molecule bonds with the ligand-binding domain, a number of structural changes are triggered in the protein structure, opening the transmembrane ion channel formed by the receptor complex. The flow of positive ions through the open channel alters the cross-membrane voltage of the neuron, which is a precondition for nervous impulse transmission.  Of the receptor activating molecules, the so-called full agonists close the ligand-binding domain entirely, and partial agonists have been shown to produce incomplete receptor activation. Antagonists, on the other hand, prevent the opening of the ion channel by keeping the ligand-binding domain open.

Pentikäinen’s project set out to establish if molecules with different levels of receptor activation can be differentiated by  computational methods, and what types of structural changes these molecules cause in the receptor. The project was an outstanding success, and in addition to clear antagonists, it was possible to separate full and partial antagonists, which have been considered difficult to classify.  The research team observed how a single hydrogen bond in the extracellular ligand-binding domain to a great extent controls the functioning of the ion channel in the cell membrane. The outcome of the study was published in the Journal of Chemical Information and Modeling.

A high calculation capacity was required for the protein-ligand complex simulations that contained thousands of atoms and were up to 100 nanoseconds in duration. The research team used some four and a half million  CPUh of CSC’s  supercomputing resources.

Grand Challenge projects are aimed at high-impact scientific research that requires significant computational or data resource quotas or levels of service. A support group is allocated by CSC to each GC project.

Postila PA, Ylilauri M, Pentikäinen OT. Full and Partial Agonism of Ionotropic Glutamate Receptors Indicated by Molecular Dynamics Simulations, Journal of Chemical Information and Modeling, 2011, 51:1037-1047.