Hydration and the Electric Field in the Voltage Sensing Domain of the Kv1.2 Channel: Quantum Calculations show S4 Doesn't Move, but Water and Protons Move

Abstract

Quantum calculations on the VSD of Kv1.2 (3Lut pdb coordinates) show several water molecules move into the VSD when the sign of the electric field goes from positive intracellularly to negative (closed). The protein backbone remains essentially immobile; S4 does not move vertically with respect to the other transmembrane segments, but may have minimal horizontal motion (parallel to the membrane surface, were the membrane included in the calculation); side chain rearrangements, however, change some intramolecular distances. We have calculated the dipole moments of the optimized structures for several cases, as well as the structures of the water clusters (these calculations:18 water molecules, 373 atoms from the protein, from the 2nd to the 4th arginine in S4, and the complementary sections of S1, S2, and S3). Rotating two water molecules in the cluster (closed conformation) sufficed for a significant change in dipole (in most calculations, counting the dipole for the entire system; dipole changes with state as well, ≤5 D for the open configuration, approximately an order of magnitude more when closed, suggesting dipole shift is part of the sensing mechanism). Several energy minima were determined; the closed configurations were several kT lower in energy than open configurations. The water behavior resembled a phase change, with finite ΔV (volume) in its overall shift in structure with changes in electric field; there is more than one energy minimum, but the change in water density is unambiguous, although the water is not ordered in either case. Gating is coupled to water via a proton shift in the lower section of the VSD (see our other abstract).