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In Silico Activation of KcsA K⁺ Channel by Lateral Forces Applied to the C-Termini of Inner Helices

Department of Biochemistry, McMaster University, Hamilton, Ontario, Canada

Correspondence: Address reprint requests to Dr. Boris Zhorov, Dept. of Biochemistry, McMaster University, 1200 Main St. W., Hamilton, Ontario L8N 3Z5, Canada. Tel.: 905-525-9140 ext. 22049; Fax: 905-522-9033; E-mail: zhorov{at}mcmaster.ca.

Crystallographic studies of K⁺ channels in the closed (KcsA) and open (MthK) states suggest that Gly⁹⁹ (KcsA numbering) in the inner helices serves as a gating hinge during channel activation. However, some P-loop channels have larger residues in the corresponding position. The comparison of x-ray structures of KcsA and MthK shows that channel activation alters backbone torsions and helical H-bonds in residues 95–105. Importantly, the changes in Gly⁹⁹ are not the largest ones. This raises questions about the mechanism of conformational changes upon channel gating. In this work, we have built a model of the open KcsA using MthK as a template and simulated opening and closing of KcsA by constraining C-ends of the inner helices at a gradually changing distance from the pore axis without restraining mobility of the helices along the axis. At each imposed distance, the energy was Monte Carlo-minimized. The channel-opening and channel-closing trajectories arrived to the structures in which the backbone geometry was close to that seen in MthK and KcsA, respectively. In the channel-opening trajectory, the constraints-induced lateral forces caused kinks at midpoints of the inner helices between Val⁹⁷ and Gly¹⁰⁴ but did not destroy interdomain contacts, the pore helices, and the selectivity filter. The simulated activation of the Gly⁹⁹Ala mutant yielded essentially similar results. Analysis of interresidue energies shows that the N-terminal parts of the inner helices form strong attractive contacts with the pore helices and the outer helices. The lateral forces induce kinks at the position where the helix-breaking torque is maximal and the intersegment contacts vanish. This mechanism may be conserved in different P-loop channels.

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