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Abstract

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.