Quantum Calculations Show How the Water at the Gate of the Voltage Gated Kv1.2 Channel Plays a Major Role in Determining Conduction through the Gate

Abstract

We have carried out quantum calculations to optimize the structure of the gate region of a Kv1.2 (with hydrogens added as in the pdb 3Lut structure) channel as well as the structure below the gate as far as the T1 segment, starting from the X-ray structure. A key result: A PVPV-->PVVV in silico mutant disrupts the water structure. The normal gate opens just enough to allow a hydrated K+ to enter the cavity that separates the gate from the selectivity filter. The mutation also alters the electrostatic potential. In addition, we have calculated the result of protonation of the H418 below the gate, which shows approximately a 3 Å rotation toward the pore on protonation, enough to alter the potential at the gate; deletion of H418 is reported to produce a non-functional channel(1). With Cl- ion at the gate, but not K+, a water structure forms in the optimized channel structure, and appears to be fairly stable; this may already select against anions. Calculations in cases that involve K+ include bond order and charges on all atoms, enabling calculation of electrical potentials. Optimizations were done initially at HF/6-31G∗ level; most have been confirmed at BLYP/6-31G∗∗ level, with little change in any case tested. Acknowledgement: Computations were done at the Brookhaven National Lab CFN cluster and the CUNY hpc facility. (1) Zhao, L.-L.; Qi, Z.; Zhang, X.-E.; Bi, L.-J.; Jin, G. Cell Biol. International 2010, 34, 433.