Accessible Requires Authentication Published by De Gruyter January 20, 2014

Probing “ambivalent” snug-fit sites in the KcsA potassium channel using three-dimensional reference interaction site model (3D-RISM) theory

Saree Phongphanphanee, Norio Yoshida, Shigetoshi Oiki and Fumio Hirata

Abstract

The potassium channel is highly selective for K+ over Na+, and the mechanism underlying this selectivity remains unclear. We show the three-dimensional distribution functions (3D-DFs) of small cations (Li+, Na+, and K+) and the free energy profile of ions inside the open selectivity filter (SF) of the KcsA channel. Our previous results [S. Phongphanphanee, N. Yoshida, S. Oiki, F. Hirata. Abstract Book of 5th International Symposium on Molecular Science of Fluctuations toward Biological Functions, P062 (2012)] indicate that the 3D-DF for K+ exhibits distinct peaks at the sites formed by the eight carbonyl oxygen atoms belonging to the surrounding peptide-backbone and residues (the cage site). Li+ has sharp distributions in the 3D-DF at the center of a quadruplex composed of four carbonyl oxygen atoms (the plane site). Na+ has a rather diffuse distribution throughout the SF region with peaks both in the plane and in cage sites. The results provide microscopic evidence of the phenomenological findings that Li+ and Na+ are not excluded from the SF region and that the binding affinity alone does not cause the ion selectivity of KcsA. In the present study, with an ion placed explicitly along the pore axis, the free energy profiles of the ions inside the SF were calculated; from these profiles we suggest a new mechanism for selective K+ permeation. According to the model, a K+ ion must overcome a free energy barrier that is approximately half that of Na+ to exit from either of the SF mouths due to the existence of an intermediate local minimum along the route for climbing the barriers.


Corresponding authors: Shigetoshi Oiki, Faculty of Medical Sciences, Department of Molecular Physiology and Biophysics, University of Fukui, Fukui 910-1193, Japan; and Fumio Hirata, College of Life Sciences, Ritsumeikan University, Kusatsu, Shiga 525-8577, Japan, e-mail: ,

A collection of invited papers based on presentations at the 33rd International Conference on Solution Chemistry (ICSC-33), Kyoto, Japan, 7–12 July 2013.

These works are supported by the Grant-in Aid for Scientific Research on Innovative Areas “Molecular Science of Fluctuations toward Biological Functions” from the Ministry of Education, Culture, Sports, Science and Technology in Japan. We are also grateful to Next Generation Integrated Nano-science Simulation Software, a project of the ministry. Molecular Graphics images were produced using the UCSF Chimera package [38].

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Published Online: 2014-01-20
Published in Print: 2014-02-01

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