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Ab Initio calculations on a proposed gating mechanism for the KcsA channel


EMSL Project ID
4796

Abstract

Abstract: The determination of the (revised) structure of the KcsA K+ channel of S Lividans, a bacterium (Zhou, Morais-Cabral et al. 2001), has made it possible to understand the location of the gating of the channel at the intracellular section of the protein. Perozo (private communication, (Perozo, Marien Cortes et al. 1999)) has found by mutation of residues in this region that one set of glutamines (Q119) and the neighboring charged residues, particularly R117,E118,E120,R121, are especially important in affecting gating. The channel, unlike most eukaryotic channels, gates with a drop in pH, suggesting immediately the titration of the glutamate residues as a possible mechanism for the role of H+ in gating. We observe that the four Q119 residues form a strong network of hydrogen bonds, and that the neighboring waters would have the opportunity to form a hydrogen bonding network. If the glutamates (especially E118) were neutralized by a drop in pH, there would be strong electrostatic repulsion. At some point, when a sufficient number of the glu residues are neutralized, the hydrogen bond network should separate. This would allow the gln side chains to bend out of the way, opening the channel for K+ ions to pass. We need to know how many protons are needed, at what pH they would add, and how strong the postulated hydrogen bond network is. Standard classical MD simulations seem to fail to provide a satisfactory answer, in spite of numerous attempts. We believe that only if the hydrogen bonding network is completely understood will there be a complete gating mechanism. This is important because the KcsA channel has considerable homology with eukaryotic channels, so that understanding the gating mechanism of this channel should be a significant start to understanding the final step in gating voltage gated, and conceivably also CNG (cyclic nucleotide gated) eukaryotic channels. We have therefore begun calculations using Gaussian03 on a truncated system that we expect will give us a preliminary understanding of the system. These calculations are, so far, successful on a preliminary level, using only HF/3-21G*, to get a starting structure for B3LYP/6-311G** calculations, which are now under way. Further work will require a large increment of computer resources.

Perozo, E., D. Marien Cortes, et al. (1999). "Structural Rearrangements underlying K+-channel gating." Science 285: 73-78.
Zhou, Y. J. H. Morais-Cabral, et al (2001) Chemistry of ion coordination and hydration revealed by a K+ channel-FAB complex at 2.0 A resolution Nature 414, 43-48

Project Details

Project type
Capability Research
Start Date
2003-10-26
End Date
2006-10-29
Status
Closed

Team

Principal Investigator

Michael Green
Institution
City College of New York

Team Members

Vasiliy Znamenskiy
Institution
City College of New York

Xavier Periole
Institution
City College of New York

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