Journal
BIOPHYSICAL CHEMISTRY
Volume 124, Issue 3, Pages 251-267Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bpc.2006.04.015
Keywords
ion channel; ion permeation; ion selectivity; potential of mean force; free energy; molecular dynamics; gramicidin
Funding
- NIGMS NIH HHS [GM62342, GM70791, R01 GM021342, GM21342] Funding Source: Medline
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Ion channels catalyze the permeation of charged molecules across cell membranes and are essential for many vital physiological functions, including nerve and muscle activity. To understand better the mechanisms underlying ion conduction and valence selectivity of narrow ion channels, we have employed free energy techniques to calculate the potential of mean force (PMF) for ion movement through the prototypical gramicidin A channel. Employing modem all-atom molecular dynamics (MD) force fields with umbrella sampling methods that incorporate one hundred 1-2 ns trajectories, we find that it is possible to achieve semi-quantitative agreement with experimental binding and conductance measurements. We also examine the sensitivity of the MD-PMF results to the choice of MD force field and compare PMFs for potassium, calcium and chloride ions to explore the basis for the valence selectivity of this narrow and uncharged ion channel. A large central barrier is observed for both anions and divalent ions, consistent with lack of experimental conductance. Neither anion or divalent cation is seen to be stabilized inside the channel relative to the bulk electrolyte and each leads to large disruptions to the protein and membrane structure when held deep inside the channel. Weak binding of calcium ions outside the channel corresponds to a free energy well that is too shallow to demonstrate channel blocking. Our findings emphasize the success of the MD-PMF approach and the sensitivity of ion energetics to the choice of biomolecular force field. (c) 2006 Elsevier B.V. All rights reserved.
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