QUANTUM CALCULATIONS ON ION CHANNELS, ESPECIALLY VOLTAGE GATED CHANNELS
EMSL Project ID
50353
Abstract
The properties of ion channel proteins, found in essentially all organisms, will be computed using quantum calculations. The principal techniques include optimization at Hartree-Fock level (determination of the structure of local energy minima) of the protein with several positions of protons on the side chains of the protein. Our recently completed studies on one 976 atom section of the voltage sensing domain (VSD) of a voltage gated channel (Kv1.2) have shown that the backbone of the VSD does not move with voltage, but side chains do, and protons attached to the side chains have their energy minima on different residues, depending on applied voltage; the protons progress through the VSD with voltage. Having determined the optimized structures, the next step is determination of accurate energy, using density functional theory with a better basis set, as well as finding bond strength and charges on atoms, using NBO calculations. We have found that the exchange and correlation energies are about an order of magnitude larger than kT at room temperature, and these terms cannot be present in any classical calculation; quantum calculations are required. Based on work completed so far, we can state that side chains can rotate, in concert with the proton transfer and the voltage shift. We expect to be able to find a complete path through the VSD, in which the proton transfers all the way to the gate, so that with the applied voltage of -70 mV intracellularly (corresponding to the normal voltage in the resting, or closed, state), ion conduction stops. With zero, or positive, voltage, the gate is open (until it inactivates) allowing conduction. We will test whether proton transfer is sufficient to account for the channel gating, contrary to the standard model of gating, which requires extensive backbone motion. Huge amounts of resources have been devoted to the question by many workers over decades. These channels are found, in one form or another, in practically every cell. Understanding their function is likely to prove the key to many human diseases (many diseases are known to be channelopathies, although this is not the focus of our interest), but also to the functioning of plants, fungi, and bacteria as well; the first X-ray structure determined was bacterial. Many bacterial channels are known, both for sodium and potassium, with strong structural similarities to animal cell channels. Understanding the channels is fundamental to understanding the metabolism of practically all organisms. The calculations we have completed so far are extensive, requiring hundreds of thousands of processor hours; the next steps are even more extensive, and will require over the next two years approximately 2 to 3 million processor hours. Memory requirements are not as far beyond normal computations; the limit is set by the processor hours available, and the speed of the processors. For this project to be completed successfully, extremely large computer facilities will be required. It will be necessary to do the complete set of calculations to compare results to the extensive experimental work that is available from many labs, and is constantly being added to, as the importance of the subject attracts many groups to the field.
Project Details
Start Date
2018-04-09
End Date
2018-09-30
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members