This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Membrane transporters and channels are responsible for moving ions and molecules from one side of the membrane to the other. This movement accomplishes a wide range of tasks from creating ionic gradients used to power cellular processes to generating electrical signals that propagate through the central nervous system. The current proposal examines the conformational changes associated with the operation of a sugar transporter, vSGLT, and the acid sensing ion channel, ASIC. Both of these membrane proteins respond to cues in the environment to switch between functionally important states. In the case of vSGLT, it must bind a sodium ion and a sugar molecule from the extracellular space and then undergo a conformational change to create a physical exit for the molecules into the cell. ASIC responds to changes in the pH of the extracellular space causing it to open or close a membrane-spanning pore through the molecule to permit the passage of sodium ions into the cytoplasm. Two outstanding questions that we intend to use computational methods to address are the long times required for molecular changes to occur and the selective nature with which these membrane proteins interact with effector molecules. We fully expect that the work outlined in this proposal will shed light specifically on the biology of vSGLT and ASIC as well as the very large class of proteins that undergo conformational changes and interact specifically with binding partners.
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