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Biophys. J. BioFAST: First Published January 13, 2006. doi:10.1529/biophysj.105.073205
© 2006 by the Biophysical Society.

A more recent version of this article appeared on April 1, 2006.
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BIOPHYSICAL THEORY AND MODELING

Role of protein flexibility in ion permeation: A case study in gramicidin A

Turgut Bastug 1, Angus Gray-Weale 1, Swarna M. Patra 1 and Serdar Kuyucak 1*

1 University of Sydney

* To whom correspondence should be addressed. E-mail: serdar{at}physics.usyd.edu.au.

Submitted on August 23, 2005
Revised on September 29, 2005
Accepted on 16 December 2005


  Abstract
Proteins have a flexible structure, and their atoms exhibit considerable fluctuations under normal operating conditions. However, apart from some enzyme reactions involving ligand binding, our understanding of the role of flexibility in protein function remains mostly incomplete. Here we investigate this question in the realm of membrane proteins that form ion channels. Specifically, we consider ion permeation in the gramicidin A channel, and study how the energetics of ion conduction changes as the channel structure is progressively changed from completely flexible to a fixed one. For each channel structure, the potential of mean force for a permeating potassium ion is determined from molecular dynamics (MD) simulations. Using the same MD data for completely flexible gramicidin A, we also calculate the average densities and fluctuations of the peptide atoms and investigate the correlations between these fluctuations and the motion of a permeating ion. Our results show conclusively that peptide flexibility plays an important role in ion permeation in the gramicidin A channel, thus providing another reason---besides the well known problem with the description of single file pore water---why this channel cannot be modeled using continuum electrostatics with a fixed structure. The new method developed here for studying the role of protein flexibility on its function clarifies the contributions of the fluctuations to energy and entropy, and places limits on the level of detail required in a coarse-grained model.

Key Words: gramicidin A, ion permeation, molecular dynamics, protein flexibility




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Copyright © 2006 by the Biophysical Society.