This Article Full Text Full Text (PDF) All Versions of this Article: biophysj.105.073205v1 90/7/2285    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bastug, T. Articles by Kuyucak, S. Search for Related Content PubMed PubMed Citation Articles by Bastug, T. Articles by Kuyucak, S.

Role of Protein Flexibility in Ion Permeation: A Case Study in Gramicidin A

Turgut Batu, Angus Gray-Weale, Swarna M. Patra and Serdar Kuyucak

School of Physics, University of Sydney, NSW 2006, Australia

Correspondence: Address reprint requests to Serdar Kuyucak, School of Physics, University of Sydney, NSW 2006, Australia. Tel.: 61-2-9036-5306; Fax: 61-2-9351-7726; E-mail: serdar{at}physics.usyd.edu.au.

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 molecular dynamics 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.

This article has been cited by other articles:

				G. Portella, J. S. Hub, M. D. Vesper, and B. L. de Groot Not Only Enthalpy: Large Entropy Contribution to Ion Permeation Barriers in Single-File Channels Biophys. J., September 1, 2008; 95(5): 2275 - 2282. [Abstract] [Full Text] [PDF]

				S.-H. Chung and B. Corry Conduction Properties of KcsA Measured Using Brownian Dynamics with Flexible Carbonyl Groups in the Selectivity Filter Biophys. J., July 1, 2007; 93(1): 44 - 53. [Abstract] [Full Text] [PDF]

				T. Bastug and S. Kuyucak Energetics of Ion Permeation, Rejection, Binding, and Block in Gramicidin A from Free Energy Simulations Biophys. J., June 1, 2006; 90(11): 3941 - 3950. [Abstract] [Full Text] [PDF]