Interchain hydrogen-bonding interactions may facilitate translocation of K(+) ions across the potassium channel selectivity filter, as suggested by synthetic modeling chemistry

A 4-fold symmetric arrangement of TVGYG polypeptides forms the selectivity filter of the K(+) channel from Streptomyces lividans (KcsA). We report the synthesis and properties of synthetic models for the filter, p-tert-butyl-calix[4]arene-(OCH(2)CO-XOBz)(4) (X = V, VG, VGY), 1–3. The first cation (Na(+), K(+)) binds to the four -{OCH(2)CO}- units, a region devised to mimic the metal-binding site formed by the four T residues in KcsA. NMR studies reveal that cations and valine amide protons compete for the carbonyl oxygen atoms, converting N—H(Val)⋅⋅⋅O⩵C hydrogen bonds to M(+)⋅⋅⋅O⩵C bonds (M(+) = Na(+) or K(+)). The strength of these interchain N—H(Val)⋅⋅⋅O⩵C hydrogen bonds varies in the order 3 > 2 > 1. We propose that such interchain H-bonding may destabilize metal binding in the selectivity filter and thus help create the low energy barrier needed for rapid cation translocation.