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Computer Simulation Studies of CLC Chloride Channels and Transporters

by Mahankali, Uma

Abstract (Summary)
In this dissertation, the CLC family of chloride channels and transporters are discussed with respect to their structure-function relationships. Here, we report the results from our computer simulation studies of the CLC proteins. We built homology models of four CLC proteins ClC-0, ClC-2, ClC-4 and ClC-5. These structures were validated and energy minimized to obtain working models for further simulations. Electrostatic calculations of the bacterial CLC homologue are presented, including the investigations on the effects of different parameters on the pKa shifts of a key glutamate residue. This residue was identified as a gate in the CLC channels and external proton-transfer residue in the CLC transporters. We found that the presence of three binding site chloride ions in the pore was required to shift the pKa of the glutamate residue up into a physiological pH range. The calculated pKa shifts were highly sensitive to the dielectric constant of the protein. Free energy barriers for the gate opening in bacterial CLC structure were estimated in protonated and unprotonated states of the side chain of the gate, Glu148. Further, the effect of chloride ions in the vicinity of the Glu148 was also examined. These computer simulations provide important tools for the ongoing studies into the structure-function relationships in CLC channels and transporters.
Bibliographical Information:

Advisor:

School:University of Cincinnati

School Location:USA - Ohio

Source Type:Master's Thesis

Keywords:clc chloride channels transporters adaptive biasing force electrostatic calculations homology modeling fast gating in

ISBN:

Date of Publication:01/01/2006

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