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Journal Article

The role of methyl–induced polarization in ion binding


Rossi,  Mariana
Theory, Fritz Haber Institute, Max Planck Society;

Tkatchenko,  Alexandre
Theory, Fritz Haber Institute, Max Planck Society;

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Rossi, M., Tkatchenko, A., Rempe, S. B., & Varma, S. (2013). The role of methyl–induced polarization in ion binding. Proceedings of the National Academy of Sciences of the United States of America, 110(32), 12978-12983. doi:10.1073/pnas.1302757110.

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The chemical property of methyl groups that renders them indispensable to biomolecules is their hydrophobicity. Quantum mechanical studies undertaken here to understand the eect of point substitutions on potassium (K-) channels illustrate quantitatively how methyl-induced polarization also contributes to biomolecular function. K-channels regulate transmembrane salt concentration gradients by transporting K+ ions selectively. One of the K+ binding sites in the channel's selectivity filter, the S4 site, also binds Ba2+ ions, which blocks K+ transport. This inhibitory property of Ba2+ ions has been vital in understanding K-channel mechanism. In most K-channels, the S4 site is comprised of four threonine amino acids. The K-channels that carry serine instead of threonine are signicantly less susceptible to Ba2+ block and have reduced stabilities. We find that these differences can be explained by the lower polarizability of serine compared to threonine as serine carries one less branched methyl group than threonine. A T->S substitution in the S4 site reduces its polarizability, which, in turn, reduces ion binding by several kcal/mol. While the loss in binding affinity is high for Ba2+, the loss in K+ binding affinity is also signicant thermodynamically, which reduces channel stability. These results highlight, in general, how biomolecular function can rely on the polarization induced by methyl groups, especially those that are proximal to charged moieties, including ions, titratable amino acids, sulphates, phosphates and nucleotides.