@article{907e6df9b4364cf1af26c2a37abe6134,
title = "Selectivity and cooperativity of modulatory ions in a neurotransmitter receptor",
abstract = "Ions play a modulatory role in many proteins. Kainate receptors, members of the ionotropic glutamate receptor family, require both monovalent anions and cations in the extracellular milieu for normal channel activity. Molecular dynamics simulations and extensive relative binding free energy calculations using thermodynamic integration were performed to elucidate the rank order of binding of monovalent cations, using x-ray crystal structures of the GluR5 kainate receptor dimers with bound cations from the alkali metal family. The simulations show good agreement with experiments and reveal that the underlying backbone structure of the binding site is one of the most rigid regions of the protein. A simplified model where the partial charge of coordinating oxygens was varied suggests that selectivity arises from the presence of two carboxylate groups. Furthermore, using a potential of mean force derived from umbrella sampling, we show that the presence of cations lower the energy barrier for anion approach and binding in the buried anion binding cavity.",
author = "Ranjit Vijayan and Plested, {Andrew J.R.} and Mayer, {Mark L.} and Biggin, {Philip C.}",
note = "Funding Information: Using extensive MD simulations and free energy calculations, we have shown that the binding site selects for smaller cations and that the predictive selectivity agrees well with experimentally determined conclusions. Furthermore, the agreement between the free energy series from different kainate receptor subtypes suggests that the selectivity is controlled by local interactions. This result is also supported by the simplified model of the binding site, where the selectivity of a Na + ion over a K + ion could be attributed to the high electronegativity of the cation binding sites held on a rigid backbone. Furthermore, we demonstrate that the presence of cations stabilizes the anion by 5 kcal/mol and also appears to reduce the barrier along a simple unbinding trajectory. We also show that, even in the presence of cations, a large barrier still persists, suggesting that anion binding may either proceed in a different conformational state of the receptor, or that the whole process follows an alternative pathway. Structural information concerning the desensitized state will help to address this question. We thank our colleagues Dr. Philip W. Fowler and Henry Chew for helpful discussions. Computations were performed on the clusters of the UK National Grid Service and the Oxford Supercomputing Centre. P.C.B. is a Research Councils UK fellow. This work was supported by the Oxford University Clarendon Fund and UK Overseas Research Students Awards Scheme (to R.V.), Wellcome Trust (to P.C.B.), and the intramural research program of the National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services (to M.L.M.). ",
year = "2009",
doi = "10.1016/j.bpj.2008.11.039",
language = "English",
volume = "96",
pages = "1751--1760",
journal = "Biophysical Journal",
issn = "0006-3495",
publisher = "Biophysical Society",
number = "5",
}