Role of methyl-induced polarization in ion binding

Abstract

The chemical property of methyl groups that renders them indispensable to biomolecules is their hydrophobicity. Quantum mechanical studies undertaken here to understand the effect 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 Ba 2+ ions, which blocks K + transport. This inhibitory property of Ba 2+ ions has been vital in understanding K-channel mechanism. In most K-channels, the S4 site is composed of four threonine amino acids. The K channels that carry serine instead of threonine are significantly less susceptible to Ba 2+ block and have reduced stabilities. We find that these differences can be explained by the lower polarizability of serine compared with threonine, because 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 kilocalories per mole. Although the loss in binding affinity is high for Ba 2+ , the loss in K + binding affinity is also significant 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, sulfates, phosphates, and nucleotides. dispersion | ion channels | methylation | quantum chemistry | density-functional theory

Effect of intrinsic and extrinsic factors on the simulated D-band length of type I collagen

“…Note that we do not include in our calculations the weak hydrogen bonds involving protein carbon atoms, although they have been proposed to contribute to triple‐helix formation . This is because the thermodynamic stability of weak hydrogen bonds emerges primarily from electronic polarization, which is not described adequately in non‐polarizable force fields . An analysis of the final 10 ns of the 1 μs trajectory shows a similar number of inter‐peptide hydrogen bonds when the monomer widens under isobaric boundary conditions.…”

The exceptionally high reactivity of Cys 621 is critical for electrophilic activation of the sensory nerve ion channel TRPA1

“…We note first that even the hydrophobic control group, CH 4 , affects ΔΔ E , although the effect is minor. We attribute this to CH 4 ’s polarizability ( Rossi et al, 2013 ). We note next that when the basic group (NH 4 + ) is placed at a distance of 6 Å, which is roughly the distance between C621 and K620 in the cryo-EM model ( Paulsen et al, 2015 ), it reduces the ΔΔ E by 1.9 kcal/mol.…”

Tailoring van der Waals dispersion interactions with external electric charges

“…We focus on one of the preferred binding sites—S4 (shown in Fig. 4a ), that is typically composed of four threonine residues that provide four backbone carbonyl oxygens and four side-chain hydroxyl oxygens for ion coordination 59 – 61 . S4 site plays a special role in the ion gating mechanism, as Ba 2+ ions can bind to this site as well, blocking K + permeation 60 , 62 .…”

“…Site-directed mutagenesis experiments suggest that threonine-to-serine (T → S) substitution in the S4 sites reduces the channel susceptibility to Ba 2+ and its overall opening probability 61 . The key role of methyl groups for understanding the polarization and as a consequence vdW interactions in Kcv channels as well as dramatic ion affinities reduction during T → S substitutions was already suggested 61 . This leads us to the question of whether an inhomogeneous electric field could have considerable effect on dispersion interactions and binding in Kcv channel beyond direct electron density polarization.…”

“…These substitutions result in minor geometry changes, so we used geometries reported in ref. 61 , modeling an ion by a point charge. Corresponding substitution binding energies of the Ba 2+ complex, where threonine groups were systematically substituted by serine groups, are shown in Fig.…”