Mutations of positively charged amino acids in the S4 transmembrane segment of a voltage-gated ion channel form ion-conducting pathways through the voltage-sensing domain, named ω-current. Here, we used structure modeling and MD simulations to predict pathogenic ω-currents in CaV1.1 and CaV1.3 Ca2+ channels bearing several S4 charge mutations. Our modeling predicts that mutations of CaV1.1-R1 (...

Voltage-gated channels open paths for ion permeation upon changes in membrane potential, but how voltage changes are coupled to gating is not entirely understood. Two modules can be recognized in voltage-gated potassium channels, one responsible for voltage sensing (transmembrane segments S1 to S4), the other for permeation (S5 and S6). It is generally assumed that the conversion of a conformat...

Since it has been shown that point mutations in the S4-S5 loop of the Shaker K+ channel may disrupt fast inactivation, we investigated the role of three conserved amino acids in IV/S4-S5 of the adult human muscle Na+ channel (L1471, S1478, L1482). In contrast to the K+ channel mutations, the analogous substitutions in the Na+ channel (S1478A/C, L1482A) did not substantially affect fast inactiva...

Most of the sequent/tableau based proof systems for the modal logic S4 need to duplicate formulas and thus are required to adopt some method of loop checking [7, 13, 10]. In what follows we present a tableau-like proof system for S4, based on D’Agostino and Mondadori’s classical KE [3], which is free of duplication and loop checking. The key feature of this system (let us call it KES4) consists...

We have acquired structural evidence that two components evident previously in the depolarization-evoked gating currents from voltage-gated Shaker K+ channels have their origin in sequential, two-step outward movements of the S4 protein segments. A point mutation greatly destabilizes the "fully retracted" state of S4 transmembrane translocation, causing instead an intermediate state to predomin...

We consider an extension of the propositional modal logic S4 which allows ♦ to act not only on isolated formulas, but also on sets of formulas. The interpretation of ♦Γ is then given by the tangled closure of the valuations of formulas in Γ, which over finite transitive, reflexive models indicates the existence of a cluster satisfying Γ. This extension has been shown to be more expressive than ...

Here we describe the phenomenon of symmetry breaking within a series of M4L6 container molecules. These containers were synthesized using planar rigid bis-bidentate ligands based on 2,6-substituted naphthalene, anthracene, or anthraquinone spacers and Fe(II) ions. The planarity of the ligand spacer favors a stereochemical configuration in which each cage contains two metal centers of opposite h...

In the topological semantics for modal logic, S4 is well-known to be complete for the rational line, for the real line, and for Cantor space: these are special cases of S4’s completeness for any dense-in-itself metric space. The construction used to prove completeness can be slightly amended to show that S4 is not only complete, but also strongly complete, for the rational line. But no similarl...

The correlation consistent composite approach (ccCA), using the S4 complete basis set two-point extrapolation scheme (ccCA-S4), has been modified to incorporate the left-eigenstate completely renormalized coupled cluster method, including singles, doubles, and non-iterative triples (CR-CC(2,3)) as the highest level component. The new ccCA-CC(2,3) method predicts thermodynamic properties with an...

Voltage-gated ion channels open in response to a change in membrane potential. The "sensor," or the channel's molecular entity responsible for the detection of voltage change, is formed by a transmembrane element, rich with basic residues, called the "voltage sensor" or the "S4 domain." The movement of the S4 drives a global conformational change leading to the opening of the permeation pathway...