Emerging Concepts in Ion Channel Biophysics

Emerging Concepts in Ion Channel Biophysics

Poster Abstracts

36-POS Board 36 Quantum Calculations on a Voltage Sensing Domain of Kv1.2: H + Transfer and Gating Current Alisher M. Kariev 1 , Michael E. Green 1 . 1 n/a, New York, USA, 2 City College of Cuny, New York, NY, USA. Quantum calculations on a 904 atom segment of the voltage sensing domain (VSD) of Kv1.2, with 24 water molecules added, starting from X-ray coordinates (pdb:3Lut), show how protons may traverse the section, and become the gating current. With the S4 segment free to move, and a -107 Vm-1 field applied (equivalent membrane potential: V≈-70 mV), the segment backbone moves <2.5 Å, and not in the intracellular direction, as required in standard models of gating. Second, we have optimized (energy minimized) structures with protons in several positions, testing whether salt bridges present in the VSD may be neutralized; earlier work has shown that salt bridges in the absence of water do not ionize (Liao and Green, CompTheoChem, 2011). Here, energy is lower for the unionized form in certain cases with V<0 (closed channel), but not with V≥0 (open channel). Specific cases which would add to gating current, including a transfer of a proton from a tyrosine (Y266) to the pre-guanidinium nitrogen of a neighboring S4 arginine, are shown, with accompanying energy for the proton in each position. For the lowest energy states, closed (-70mV) the charges on Y266, R300, and E183 are 0,0,0; at 0 mV (open), -,+,0, respectively (nominal charges—actual charges are not integral). Open energy is ≈15kBT higher. The proton appears able to move to E183 by way of R300, providing in total about 0.6 charges of gating current. Optimization to get structure used HF/6-31G*, followed by more accurate energy calculation at B3LYP/6-31G**, plus NBO for atomic charges. Additional cases have been calculated, including some with V=+70mV; the open and closed cases shown above have the lowest energy of a substantial set of plausible states.

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