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Standard models of ion channel voltage gating require substantial movement ofone transmembrane segment, S4, of the voltage sensing domain. Evidence comesfrom the accessibility to external methanethiosulfonate (MTS) reagents of thepositively charged arginine residues (R) on this segment. These are firstmutated to cysteines (C), which in turn react with MTS reagents; it is assumedthat the C is passively carried in the S4 movement, becoming accessible on oneside or the other of the membrane. However, the Rs were salt bridged tonegatively charged residues on other transmembrane segments, or hydrogenbonded, while C reacts as a negative ion. The space available for MTS is fairlyclose to the difference in volume between the large R residue and much smallerC, so the MTS is not severely sterically hindered. A reagent molecule can reacha C side chain; the C can react if not repelled by a negative charge from theamino acid to which the R had been salt bridged. Nearby protons may also makereaction possible unless the C itself is protonated. Therefore interpretationof the C substitution results requires reconsideration. To test the idea wehave done quantum calculations on part of a mutated S4 and the nearby sectionof the channel. The mutation is R300C of the 2A79/3Lut structure, a mutationthat would be done to test MTS reagent access; there is a large cavity wherethe R is replaced by C. Two quantum calculations show a substantial differencein the structure of this cavity with 2 water molecules compared to 4. Thissuggests that the structure, and presumably reaction probability, could dependon water molecules, very likely also protons, in or near the cavity that theR300C mutation produces.

Quantum Calculations Show Caution Is Needed In Interpreting Methanethiosulfonate Accessibility Experiments On Ion Channels